Copy Number Variant Grid

This page provides the ability to:

• Sort variants by Tier
• Review the copy number variants identified by DRAGEN CNV as part of the Genomics England Rare Disease Pipeline
• Review additional annotations and linkouts to external resources for each variant (see CNV Grid Guide below for further details)
• Assign an ACGS/ACMG classification to a variant, including selecting a contribution to phenotype, validation details, and adding a comment (see the recording interpretation page)
• Exclude a variant, with reasoning and comment (see the recording interpretation page)
• See a history log of interpretation actions

N.B. Tiered CNVs now display as 1/2 instead of A/B. Cases processed by the pipeline prior to the 4.3 New IB release will continue to display as Tier A / Tier B instead of Tier 1 / Tier 2. Please see the limitations page for further details.

N.B The New IB supports cases with SNVs that were processed since release 4.0, CNVs that were processed since release 4.2, and cases with Tiered STRs that were processed since release 4.3. Any cases that do not fit these criteria are not supported by the product, therefore it will not be possible to analyse them in the New IB, and alternative existing systems should be utilised to analyse the case.

CNV grid guide

The order of columns in the CNV grid can be changed using the column headers. This will persist when you navigate around the case, so you can click onto a different page and come back to the CNV grid and your column order will remain intact. Please note however, that should you refresh the page, open the case in a new tab, or log out (/be logged out of) the system then log back in again and reopen the same case, then the column order will reset back to the default.

20 variants are shown by default, and more are loaded dynamically when scrolling to the bottom of the page.

Please use the below key in conjunction with the below sections to learn more about the columns in the variant grid.

Key

#	Section	Description
1	Actions	A Classify button which can be clicked to open the classification drawer, and changes to display the classification of the variant once it has been assigned (for further details see the recording interpretation page).
2	Tier	This can be Tier A, Tier B, Tier Null, or "-" for untiered variants or variants that do not fall within a gene. For further details, please visit the Tier section below.
3	Genomic region / Cytoband	The genomic region and cytoband of the variants, with a button which displays a linkout to IGV (for read depth investigation). There is also a button that opens a menu containing further links to external databases and resources (DECIPHER (browser), gnomAD CNV, gnomAD SV, UCSC and DGV) for the variant, and a button to copy the variant coordinates in Alamut format.
4	Size (bp)	Length of the copy number variant in base pairs.
5	Type / Copy number	The type of the copy number variant. Loss (deletion CNV) or Gain (duplication CNV). The copy number state is indicated by the number in brackets next to the type.
6	Genes	HGNC gene symbol(s) which the variant affects. We show the first four affected genes (additional genes are indicated with a "+n" pill, with n being the number of genes), with green genes always displayed first. Clicking on any gene pill (or +n pill) will open the gene overlay (multi-gene overlay by default). For further details, please visit the genes section below.
7	Gene colour and exon overlap	Genes in Tiered variants are coloured green according to their PanelApp green gene status. For further details, please visit the genes section below. The E symbol in the gene pill represents that the CNV has exonic overlap with at least one transcript for that gene. If that transcript is also a MANE transcript (MANE Select or MANE Plus Clinical), then we also see a M symbol next to the E.
8	Protein coding genes	The number of genes that the CNV affects with that have at least one transcript with a protein coding biotype.
9	OMIM associated diseases	Count of associated diseases for the gene in OMIM. For further details, please visit the OMIM section below.
10	Regions	PanelApp ISCA regions the CNV affects. The region pill is coloured green according to its PanelApp green gene status. For further details, please visit the regions section below.
11	Allele frequency (Loss only)	Frequency track - Displays the percentage of individuals in a reference dataset who carry a copy loss CNV that reciprocally overlaps the query CNV. Reciprocal overlap - Calculated based on CNVs that overlap the query CNV by at least 50% in both directions. These columns will only be populated where the CNV is a copy loss variant - for copy gain variants, a - will be visible. The frequency dataset only contains PASS variants. In the case where there is no data for a PASS variant, a "-" will be displayed. The vast majority of non-PASS variants will have no frequency data (i.e. "-"), however some non-PASS variants will have frequency data in the case where that non-PASS variant overlaps a PASS variant that is present in the frequency dataset.
12	Individuals with CNV (Gain only)	Frequency track - Displays the percentage of indivduals in a reference dataset who carry a copy gain CNV that reciprocally overlaps the query CNV. Reciprocal overlap - Calculated based on CNVs that overlap the query CNV by at least 50% in both directions. These columns will only be populated where the CNV is a copy gain variant - for copy loss variants, a - will be visible. The frequency dataset only contains PASS variants. In the case where there is no data for a PASS variant, a "-" will be displayed. The vast majority of non-PASS variants will have no frequency data (i.e. "-"), however some non-PASS variants will have frequency data in the case where that non-PASS variant overlaps a PASS variant that is present in the frequency dataset.
13	QC filter	Indicates whether the variant passed QC filters applied during the analysis. Obtained from the VCF file.

SortingFiltersTierGenesOMIMRegions

Sorting

By default, all variants are sorted by Tier ascending and by variant coordinates. Variants can be sorted by Tier ascending or descending by using the arrow icon or menu in the column headers.

Filters

Filters can be used to narrow the variants displayed in the variant grid to variants of interest with specific selected attributes. The filters are located above the grid column headers.

The number of variants returned by the filters, and number of variants currently visible in the grid, is highlighted by the counts above the applied filters.

Applied filters will persist when you navigate around the case, so you can click onto a different page and come back to the SNV grid and the same filters will still be applied. Please note however, that should you refresh the page, open the case in a new tab, or log out (/be logged out of) the system then log back in again and reopen the same case, then the applied filters order will reset back to the GEL default filters.

For further details on various aspects of the filtering behaviour, please view the tabs below.

N.B. Application of filters does not perform any re-Tiering of variants in the case

GEL defaultsRemove filtersVCF filterTier filterSizeTypeGenes filterFilter combinations

GEL default filters

A pre-set combination of filters, GEL default filters, are applied to the SNV grid by default in order to restrict the visible variants to those that are of interest for interpretation, and reduce noise. The set of default filters are as follows:

• VCF filter: PASS
• Tier: Tier 1 / A, Tier 2 / B

When GEL default filters are active, GEL default filter applied is visible at the top of the grid. Additional filters can then be selected, or one or multiple of the GEL default filters deselected. Custom filters applied will then be visible at the top of the grid.

If the GEL default filters or custom filters return no variants, this is clearly indicated by a message within the grid.

Removing filters

Filters can be removed easily by:

• Deselecting the filter selection or clicking clear within the multi-select drop-downs
• Clearing the text box manually, or clicking clear, within the Size filter drop-down
• Clicking the Reset to default button if custom filters have been applied, which reverts the filters back to the GEL default filters
• Clicking the Clear all button if any filters are applied, which removes all applied filters including any GEL defaults

If all filters have been removed, No filters applied will be visible at the top of the grid.

VCF filter

Variants can be filtered based upon whether they passed QC filters applied during the analysis. This is an annotation produced by the Genomics England Rare Disease Pipeline which originates from the VCF file. There are 2 selection options (see below). If both are selected, variants will be displayed that match either selection.

• VCF filter PASS
• VCF filter non-PASS

Tier filter

Variants can be filtered based on their Tier as assigned by the Genomics England Rare Disease Pipeline. There are 4 selection options (see below). This filter works at the Tiering prioritisation result (previously known as Report Event) level, so if a variant has any Tiering prioritisation result that match that Tier, then the variant will be displayed within the filter results. If multiple are selected, variants will be displayed that match any selection. N.B. If Tier Null is selected, and the variant has a Tier Null prioritisation result but also has a higher Tiering prioritisation result (for example Tier 1 / A), then that variant will still be displayed within the grid.

N.B the Tier selections are displayed as 'Tier 1 / A' and 'Tier 2 / B' because processed by pipeline prior to version 4.3 of the New IB release will continue to display CNVs as Tier A / Tier B instead of Tier 1 / 2. These are equivalent Tiers. Please see the limitations page for further details.

• Tier 1 / A
• Tier 2 / B
• Tier Null
• Untiered

Size filter

Variants can be filtered by size using either base pairs (bp) or kilobase pairs (kb). You can enter a minimum size, a maximum size, or both:

• Minimum size: returns variants greater than or equal to the value entered.
• Maximum size: returns variants less than or equal to the value entered.

When both values are entered, only variants within the specified size range are returned. After entering the required values, select Apply to apply the filter.

Type filter

Variants can be filtered by type using the following drop-down options:

• Loss / Deletion
• Gain / Duplication

Select one option to display variants of that type. If both options are selected, all CNVs will be displayed.

Genes filter

The Genes filter allows variants to be filtered using an HGNC gene symbol or Ensembl gene ID.

The available options are generated from genes annotated against CNVs in the case, rather than from a complete reference list. The options may therefore differ between cases and between the SNV and CNV grids, and a gene will not appear where it has not been annotated against any CNV in the case. For genes with many associated identifiers, further options are loaded as the dropdown is scrolled. The filter query uses both the gene symbol and Ensembl ID to ensure that all matching variants are returned.

Begin typing a gene symbol or Ensembl ID to display matching options. Multiple genes can be selected, and CNVs annotated with any of the selected genes are returned.

The filter includes CNVs annotated as overlapping the selected gene, including CNVs located up to 5 kb upstream or downstream of the gene. These can be identified by their upstream or downstream consequence annotations.

Only gene symbols and Ensembl IDs annotated at the point the case was ingested can be searched. The filter does not map between previous and current gene symbols or Ensembl IDs. Searching with an alternative, historical or subsequently updated identifier may therefore return no matching option, even where the gene is present under a different identifier.

Several genes may be annotated against a CNV. Only the first 4 annotated genes are displayed directly in the grid. Therefore it is important to note that the gene matched by the filter query may not be immediately visible in the grid and may only be visible when opening the gene overlay.

When the Genes filter is combined with the Tier filter, each filter is evaluated independently against the CNV. For example, a CNV overlapping two genes may have a Tier 1 report event associated with one gene but no tiering report event associated with the other. Filtering for the untiered gene together with Tier 1 may still return the CNV because the Genes filter matches any gene overlapped by the variant, while the Tier filter matches the separate Tiering report event. Tiering information and the associated genes should always be reviewed to confirm why the CNV matched the filter query.

Tiering is based on the PanelApp version used when the case was processed, whereas gene colours reflect the latest PanelApp annotations available at case ingestion. In the unlikely event that a gene’s PanelApp status changed between Tiering and ingestion, the latest gene colour may not correspond to the original tiering result.

Filter combinations

Filters can be applied in combinations to further narrow down the number of variants displayed within the grid. For example, if the VCF pass filter was applied at the same time as the Tier filter, the variant would need to meet both criteria to be displayed within the grid in the filter results. There is a notable caveat to this:

#	Filter combination	Behaviour
1	Genes + Tier (and/or penetrance + segregation)	The Genes filter and report-event filters are evaluated independently against the variant. Variants are returned where they overlap any selected gene and separately have a Tier prioritisation result matching the selected Tier and, where applied, penetrance and segregation values. These criteria do not need to relate to the same gene. For example, a variant may be Tier 1 in one gene but returned when filtering for a different overlapped gene. Review the Tiering information and associated gene to confirm why the variant matched.

Tier

This can be Tier A, Tier B, Tier Null, or "-" for untiered variants or variants that do not fall within a gene. When clicking on the tooltip next to the Tier, the Tier overlay opens.

For details on how to sort by Tier, please visit the sorting section.

Tier overlay

The Tier overlay displays details about the Genomics England Tiering outcome for the variant.

The highest Tier assigned to the variant and the clinical indication for the proband are displayed at the top of the overlay.

Below this we see all prioritisation results (previously known as Report Events) for the variant displayed in a table; the entity and panel considered by Tiering as part of the finding are displayed per prioritisation result.

Key

#	Section	Description
1	Highest Tier	The highest Tier assigned to the variant by Genomics England Rare Disease Tiering.
2	Clinical indication	The clinical indication for the proband.
3	Tier	Tier assigned by Genomics England Rare Disease Tiering.
4	Entity	Gene or region affected by the CNV for the Genomics England Rare Disease Tiering result.
5	Entity colour	The entity pill is coloured green when the entity is green in at least one PanelApp panel (/superpanel) of the most recent version at the time of case ingestion, where that panel is also a panel that has been applied to the case.
6	GMS panel name	Name of the GMS panel applied to the patient that is associated with the Genomics England Rare Disease Tiering result, with a link to the GMS signed off PanelApp panel.
7	Links to GEL Rare Disease Genome Analysis Guide	Links to the relevant pages in the Genomics England Rare Disease Genome Analysis Guide.

Genes

HGNC gene symbol(s) which the variant affects; affected genes are displayed in the grid. This is different to the behaviour in the SNV grid - here we display the first 4 genes, with green genes always displayed first, and a +n pill to represent the number of further genes affected by the CNV. Those that are green in a PanelApp panel are displayed first.

Clicking on the gene, or +n in the Genes column opens the gene overlay.

Gene colour

Green genes are always displayed first and are denoted by the gene pill being coloured green. If any of the further genes represented by the +n pill are also green in a PanelApp panel, then the +n pill will also be displayed green.

Multi gene overlay

The multi-gene overlay contains the key information for each gene affected by the CNV, in a single table. Those genes that are green in PanelApp are ordered first in the table. More detailed information for each individual gene is accessible in the single gene overlay.

Key

#	Section	Description
1	Total number of genes	Total number of genes that the CNV affects.
2	Variant coordinates	Coordinates for the CNV.
3	Gene name / header	The gene names can be seen along the top of the overlay - these are clickable, with each tab displaying the relevant information for that gene. Green genes are always ordered first.
4	Gene colour	The gene pill is coloured green when the gene is green in at least one PanelApp panel of the most recent version at the time of case ingestion.
5	Exon overlap	E symbol in the gene pill represents that the CNV has exonic overlap with at least one transcript for that gene. If that transcript is also a MANE transcript (MANE Select or MANE Plus Clinical), then we also see a M symbol next to the E.
6	Gene	HGNC gene symbol which the variant affects. Gene is coloured according to PanelApp green gene status in the same way as the gene symbols in the header.
7	PanelApp panels	PanelApp panels for the gene (including version and a link-out to the PanelApp page for the panel). If the gene is present in no PanelApp panels, then a - is displayed. A maximum of 2 PanelApp panels are displayed in the grid. If the gene is in any further PanelApp panels, the number of additional panels is denoted by +n. (N.B. This count only includes panels, not superpanels)
8	Impacted exons (MANE)	Displays the exons that are overlapped by the CNV for any MANE transcripts for that gene. A M or M+ icon will be displayed next to the exon overlap to denote whether the transcript is MANE Select or MANE Plus Clinical. If no exons are overlapped in MANE transcripts, a - will be displayed.
9	OMIM associated diseases	Displays any diseases associated with the gene in OMIM, and a link-out to the OMIM page for each disease. A maximum of 2 associated diseases are displayed in the grid. If the gene is associated with more than 2 diseases in OMIM, the number of additional diseases is denoted by +n.
10	Protein coding	Denotes whether the gene is protein coding (i.e. has any transcript with a biotype that is protein coding).
11	Links	Linkouts to external resources and databases for the gene (OMIM, PubMed, PanelApp, ClinGen, DECIPHER).

Single gene overlay

The gene overlay which displays relevant information for the gene.

This includes Ensembl IDs for the gene and transcripts, PanelApp panels the gene is present in, OMIM associated diseases for the gene, the c. HGVS nomenclature for the CDS change, the p. HGVS nomenclature for the protein change, and links to external resources for the gene (OMIM, PubMed, PanelApp, ClinGen, DECIPHER). All variants are annotated with PanelApp panels upon case ingestion, with the underlying dataset used for annotation updated with the most recent PanelApp data every hour (data is static once the case is ingested into the New IB). For further details, see the annotations page.

The gene names can be seen along the top of the overlay; a variant can be associated with more than one gene. Gene names are clickable, with each page displaying the relevant information for that gene.

Key

#	Section	Description
1	Gene count, and variant	Header consisting of a count of the associated genes, and the variant coordinates
2	Gene tabs	Tabs for each gene the variant is associated with, plus a tab for the multi-gene display. These are clickable, with each tab displaying the relevant information for that gene.
3	Gene colour	The gene pill is coloured green when the gene is green in at least one PanelApp panel of the most recent version at the time of case ingestion.
4	Exon overlap	E symbol in the gene pill represents that the CNV has exonic overlap with at least one transcript for that gene. If that transcript is also a MANE transcript (MANE Select or MANE Plus Clinical), then we also see a M symbol next to the E.
5	Gene ID	Ensembl gene ID.
6	Links	Linkouts to external resources and databases for the gene (OMIM, PubMed, PanelApp, ClinGen, DECIPHER).
7	PanelApp panels	This section displays the PanelApp panels for the gene (including version and a link-out to the PanelApp page for the panel). If the panel is present in any superpanels, these are listed within the row under a Superpanels header. For each panel, we see the gene rating (green, amber, red), and PanelApp's MOI for the gene. If there is no MOI recorded in PanelApp, then this will be displayed as Unknown. If the gene has been removed from the panel in the most recent version at the time of case ingestion, then a '-' is displayed in the Gene status column, and the Gene MOI will be displayed as Unknown. If the gene is present in no PanelApp panels, then None is displayed in place of all data.
8	OMIM associated diseases	Displays any diseases associated with the gene in OMIM, as well as the gene-phenotype mode of inheritance, and a link-out to the OMIM page for each disease. Where there is more than 1 associated disease the data is displayed in a table, and pages of the table can be navigated between using the arrow buttons.
9	Transcript information	Table containing details of transcripts for that gene which overlap the variant. A '-' in the table indicates that this data is not available for the transcript. Transcripts are ordered by the following priority: MANE Select, MANE Plus Clinical. Any transcripts that do not match these criteria are displayed unordered.
10	Transcript / RefSeq Match	Ensembl transcript ID is provided for each transcript, and RefSeq NM number is provided for MANE transcripts. These provide linkouts to the respective transcript pages. RefSeq transcript IDs are only provided for MANE transcripts, as only these guarantee 100% sequence identity between the respective Ensembl and RefSeq transcript IDs. If the transcript is MANE then a flag will be displayed (M for MANE Select and M+ for MANE Plus Clinical). If more than 5 transcripts exist, then these can be navigated through using the arrows at the bottom of the table.
11	Exon overlap	The specific exons in that transcript that are overlapped by the CNV.
12	Impacted region	The region of the transcript that is impacted by the CNV: Full transcript, Partial coding sequence, Partial non-coding sequence, Not applicable.
13	Transcript biotype	Indicates the type of transcript; this can indicate whether it is coding or non-coding and its role.
14	Protein ID (Ensembl ID)	Ensembl ID for the protein produced by the transcript.

OMIM associated diseases

There is a count of associated diseases in OMIM for each gene visible in the row for the variant.

Clicking the i icon opens the OMIM overlay. Different from the SNV grid, the OMIM overlay in the CNV grid displays all gene-disease associations for the variant, across all genes associated with the variant.

OMIM data is annotated at the point of case ingestion, with the underlying data used for annotation being updated with each New IB release. For further details, see the annotations page.

OMIM overlay

The OMIM overlay displays each disease associated with any gene in OMIM that is associated with the variant, the gene-phenotype mode of inheritance, and a link-out to the OMIM page for each disease (N.B. this is different to the SNV overlay where the associations are displayed for a single gene only). If there is no mode of inheritance in OMIM for an associated disease then Unknown will be visible. The pages of the table can be navigated between using the arrow buttons. The associated diseases are ordered with those associated with a green gene coming first, and then ordered alphabetically by associated disease name.

Where a disease is associated with multiple genes for that variant, multiple genes will be displayed next to that disease in the Gene column.

Regions

PanelApp ISCA regions the CNV affects. Where the CNV does not overlap a region, a - is displayed.

Region colour

The region pill is coloured green when the region is green in at least one PanelApp panel of the most recent version at the time of case ingestion.

Region overlay

The region overlay which displays relevant information for the region. This includes the ISCA region name, the required percentage of overlap, PanelApp panels the region is present in, and Haploinsufficiency or Triplosensitivity Score, as well as link-outs to PanelApp and ClinGen for the region. The data used for PanelApp panel annotation is updated every hour (data is static once the case is ingested into the New IB).

There is a region overlay per region - if the CNV affects multiple regions, the overlay for one would need to be closed in order to view the overlay for the other.

Key

#	Section	Description
1	Region name / header	The descriptive, cytogenetic name for the region can be seen along the top of the overlay. A variant can be associated with more than one region, but to see information for a second region the overlay should be exited and the other region name clicked on.
2	Region colour	The gene pill is coloured green when the gene is green in at least one PanelApp panel of the most recent version at the time of case ingestion.
3	Region coordinates	Coordinates for the region.
4	ClinGen ISCA region ID	ClinGen curated identifier for the region.
5	Required percentage overlap	The minimum percentage of the defined genomic region that needs to be covered by a CNV for it to be considered clinically significant.
6	Links	Linkouts to external resources and databases for the region (PanelApp and ClinGen).
7	PanelApp panels	This section displays the PanelApp panels for the region (including version and a link-out to the PanelApp page for the panel). If the panel is present in any superpanels, these are listed within the row under a Superpanels header. For each panel, we see the region status (green, amber, red), and PanelApp's MOI for the region. If there is no MOI recorded in PanelApp, then this will be displayed as Unknown. If the region has been removed from the panel in the most recent version at the time of case ingestion, then a '-' is displayed in the Region status column, and the Region MOI will be displayed as Unknown.
8	Haploinsufficiency / triplosensitivity score	The score for the region, as provided by PanelApp. Possible options for haploinsufficiency are: 3 (Sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype) or 30 (Gene associated with autosomal recessive phenotype). Possible options for triplosensitivity are: 2 (Emerging evidence suggesting dosage sensitivity is associated with clinical phenotype), 3 (Sufficient evidence suggesting dosage sensitivity is associated with clinical phenotype).

Abbreviations

Abbreviation	Definition
ACGS	Association for Clinical Genomic Science
ACMG	American College of Medical Genetics and Genomics
CDS	Coding DNA Sequence
CIP-API	Genomics England Clinical Interpretation API
CNV	Copy Number Variant
CVA	Clinical Variant Ark
EQ	Exit Questionnaire
New IB	New Interpretation Browser
GEL	Genomics England
GMS	Genomic Medicine Service
GLH	Genomic Laboratory Hub
HGVS	Human Genome Variation Society
HTML	Hyper Text Markup Language
HSCN	Health and Social Care Network (N3)
IGV	Integrative Genomics Viewer
IB	Interpretation Browser
IP	Interpretation Portal
NGIS	National Genomics Informatics System
PID	Patient Identifiable Data
QC	Quality Control
SoF	Summary of Findings
SO	Sequence Ontology
SNV	Single Nucleotide Variant
SV	Structural Variant
TOMS	Test Order Management System
UAT	User Acceptance Testing
VCF	Variant Call Format File
VILs	Variant Interpretation Logs
WGS	Whole Genome Sequencing