Variant List Germline CNV

From this page, users can:

• Review the germline copy number variants identified by DRAGEN for cases ingested after 6.12.0 release
• Review the additional annotations for each of these variants
• Apply certain filters
• Search for specific variants within a certain chromosome, region or gene
• View Ensembl or RefSeq transcript identifiers
• Sort the list of variants (e.g. by tier, copy number, or size)
• Flag a variant
• Add or remove a variant from the GTAB summary
• Add a comment and assign an ACGS classification to a variant
• Report whether the variant has been tested by another method i.e., Standard of Care Testing
• Report whether a variant is likely to be an artefact or a true variant

Variant Grid GuideSearchingSortingFilteringVariant InterpretationAdding Variants to the GTAB summaryPage Errors

Variant Grid Guide

Key

#	Section	Description
1	Filters	Filters applied to the genomic dataset, by default we will show all germline copy number variants in tier I and III. Click ‘filters’ to see all available filter options.
2	Search	Search for variants within specific genomic regions, chromosomes or genes. The format for genomic regions is e.g.17:41196312-41277500 and 17 for chromosomes. Only results within the applied filters will show up.
3	Clear Filters	Clear any filters applied to the variant list as shown. By default, the variant list will be filtered to display variants in genes belonging to Tier 1 and Tier 3.
4	Actions	Actions including: flagging variants, adding comments, and adding or removing variants from the GTAB summary. The Actions buttons are present for each variant and the action selected only applies to the variant you are interacting with.
5	Tier and gene	Tier and HGNC gene symbol(s) which the variant affects. We show the affected genes in the highest tier.
6	GRCh38 coordinates	Coordinates of the variant. Clicking the IGV icon will show the variant in IGV.
7	Chromosomal bands	The chromosomal band(s) overlapping this variant.
8	Variant type / Copy number	Variant type for this CNV: Gain, Loss, or copy neutral loss of heterozygosity (LOH). Followed by copy number.
9	Size (KB)	Size of the CNV in kilobases.
10	Confidence / Support	CNVs will have a confidence value assigned to indicate whether the call is High or Low confidence. For Dragen calls, "High" and "Low" indicate high and low confidence variants corresponding to PASS variants and all other variants, respectively.
11	VCF filter	Shows whether the variant has passed the pipeline filters. For variants that haven’t passed, the reason is shown in red.
12	QC flag	Flags that indicate a variant call may be of a lower quality and at greater risk of being a false positive. Hover over the QC flag for a description.
13	Population frequencies (AF/AUC)	Two different methods are used to calculate allele frequencies for CNVs: reciprocal overlap using an 80% threshold (AF) and area under the curve (AUC). See the Cancer Genome Analysis Guide for more information about each method. CNV frequencies were calculated using 5,415 germline samples from unrelated individuals (participants in the Cancer program of the 100,000 Genomes Project and the COVID-19 research project).
14	Classification	The assigned ACGS tiering of a variant. Please refer to the Variant Interpretation section for more information.

Tip: Open the transcript overlay

On your variant of interest, click any of the HGNC gene symbols shown under the Tier / Gene column (section 5 of the Variant grid guide) to open the transcript overlay (example shown below).

Searching

You can use the search bar to search for variants by gene symbol, coordinates, or chromosome. e.g.:

• TP53
• 17:7660779-7688538
• 17

Searching

Searching will filter the variant list to variants that match the search terms. If no variants are returned, there may be no variants in the chromosome, region or gene specified.

Sorting

By default, all variants are sorted by tier and coordinates. You can sort the list of germline copy number variants by tier, copy number and size. To change the order of the variants follow these steps:

1. In any column with an arrow icon, click the column menu (icon shown below).
2. Select the item you want to sort the variant by e.g. size (see example shown below).

3. Change the order to ascending or descending by clicking the desired option.

   

Sorting

Only one sort can be activated at the time. By default, the first 10 variants are shown, sorted by tier and coordinates. To see the remaining variants, scroll to the bottom of the page and new variants will continue to load.

Applying Filters

You can filter the list of germline CNVs by tier. By default we will show all tier 1 and 3 germline CNVs that passed the quality checks of the pipeline.

To edit the filters:

1. Click Filters.

2. Edit the filter settings by checking or unchecking the options of interest (Filters section 2).

3. Click Apply filters. The newly selected and applied filters will appear as pills on top of the variant grid.

Counts

The count on the top right of the variant grid shows the number of variants remaining after filters have been applied. The total number is the number of variants the pipeline identified before any quality checks have been applied.

Removing Filters

Filters can be removed individually or all at once.

• To remove all filters at once, click Clear filters (Variant grid guide section 3).
• To remove specific filters, click the X in the filter pill of interest (e.g. Tier 3 filter pill shown below)

No Filters Applied

When there are no filters applied or visible, all variants with both pass and non-pass status are shown.

Filters

Key

#	Section	Description
1	Close icon	Closes the filter panel on the right, changes to the filter settings won’t be applied.
2	Tier	Filter variants by tier e.g. 1 or 3. Unticking all tier options will remove any tier filter and include all untiered variants in the list.
3	Unselect all or Apply filters	Unselect all: removes all selected filters. Apply filters: applies selected filters to the variant list.

Variant Interpretation

You can add interpretations and comments corresponding to a variant in the variant list using the Interpretation drawer.

To open the Interpretation drawer:

1. On your variant of interest, click Classify/Edit Classification (icon shown below)

2. The Interpretation drawer will open on the right of the screen

   

Tip

Please refer to the following GTAB-related section to know how to add a germline CNV and its interpretation to the GTAB summary.

Variant QualityClassifyingValidationActionabilityComments

Artefact AssessmentArtefact Reasons

Artefact Assessment

To indicate whether the variant is likely to be a technical artefact or a true variant:

1. Select one option from the Artefact assessment dropdown list.
2. The selection will automatically save and the Saved icon will appear once saved.
3. All changes will be stored in the Interpretation drawer history.

Info

If a variant has been marked as a likely artefact in step 1, please refer to the Artefact reasons section.

Artefact Reasons and Artefact Comments

If a variant has been marked as a likely artefact, the Interpretation drawer will display an additional field: Artefact reasons. To indicate the reason why the variant is likely to be a technical artefact:

1. Select one or multiple options from the Artefact reasons dropdown list.
2. The selection will automatically save and the Save icon will appear once saved.
3. Type a comment in the Artefact comment text box to support the options selected in the previous step and click Save comment.
4. All changes will be stored in the Interpretation drawer history.

Warning

Updating the artefact assessment to "True variant" will remove the artefact reasons and comment data from the Interpretation drawer but it will still be available in the Interpretation drawer history.

Tip

Please refer to the Comments section to know how to edit and delete previous artefact comments.

Classifying

To view or add classifications:

1. Select one option from the ACGS classification dropdown list.
2. The selection will automatically save and the Save icon will appear once saved.
3. All changes will be stored in the Interpretation drawer history.

ValidationAssay Type

Validation

To indicate whether the variant has been validated:

1. Select one option from the Has this variant or entity been tested by another method (either prior to or following receipt of this WGA)? dropdown list.
2. The selection will automatically save and the Saved icon will appear once saved.
3. All changes will be stored in the Interpretation drawer history.

Info

If in step 1 you indicated that the variant has been validated by another method (prior or post WGA), please refer to the Assay Type section.

Assay Type and Assay Comment

If the variant has been validated by another method, the Interpretation drawer will display an additional field: Assay type. To select which assay type(s) the variant has also been detected in:

1. Select one or multiple options from the Assay type dropdown list.
2. The selection will automatically save and the Save icon will appear once saved.
3. Type a comment in the Assay comment text box to support the options selected in the previous step and click Save comment.
4. All changes will be stored in the Interpretation drawer history.

Warning

Updating the validation to any of the "No" options will remove the assay type and comment data from the Interpretation drawer but it will still be available in the Interpretation drawer history.

Tip

Please refer to the Comments section to know how to edit and delete previous assay comments.

Select Actionability Options and Add Actionability and Usability Comments

To enter the type of potential actionability associated with a variant and add actionability and usability comments:

1. Select one or multiple options from the Type of (potential) actionability dropdown list.
2. The selection will automatically save and the Saved icon will appear once saved.
3. Type a comment in the Actionability comment text box to support the actionability options selected in the previous step and click Save comment.
4. Select one option from the How has/will this potentially actionable variant or entity been/be used? dropdown list.
5. The selection will automatically save and the Saved icon will appear once saved.
6. Type a comment in the Usability comment text box to support the options selected in the previous step and click Save comment.
7. All changes will be stored in the Interpretation drawer history.

Tip

Please refer to the Comments section to know how to edit and delete previous actionability and usability comments.

Add Artefact, Assay, Actionability, Usability or Analysis Comments

To add an artefact, assay, actionability, usability, or analysis comment to any variant:

1. Type your comment in the Artefact, Assay, Actionability, Usability, or Analysis comment text box.
2. Click Save comment.
3. The comment is added to the corresponding section together with the name of the user who added the comment and a date-timestamp to indicate when the comment was added to the variant.
4. Only the last comment will be seen under the corresponding text box. Previous comments can be seen in the Interpretation drawer history.

Info

The Artefact comment text box only appears after selecting the "Likely artefact" option from the Artefact assessment dropdown list.

The Assay comment text box only appears after selecting any of the "Yes" options (validated prior or post WGA) from the Has this variant or entity been tested by another method (either prior to or following receipt of this WGA)? dropdown list.

The Actionability comment text box only appears after selecting one option from the Type of (potential) actionability dropdown list.

The Usability comment text box only appears after selecting one option from the How has/will this potentially actionable variant or entity been/be used? dropdown list.

Edit Previous Artefact, Assay, Actionability, Usability or Analysis Comments

To edit a previous artefact, assay, actionability, usability, or analysis comment:

1. On your comment of interest, click the icon next to the date-timestamp (icon shown below).
2. Click Edit.
3. Make your changes to the previous comment.
4. Click Save comment.

Note

You can only edit your own comments.

Delete Previous Artefact, Assay, Actionability, Usability or Analysis Comments

To delete a previous artefact, assay, actionability, usability, or analysis comment:

1. On your comment of interest, click the icon next to the date-timestamp (icon shown below).
2. Click Delete.
3. In the confirmation pop-up message that appears, click Delete.

Note

You can only delete your own comments.

Adding Variants to the GTAB summary

You can add any germline CNV and its interpretation to the GTAB summary from the variant grid or interpretation drawer.

To add a germline CNV to the GTAB summary:

1. On your variant of interest, click Add to GTAB report (icon shown below) from the variant grid or Interpretation drawer
2. Go to the GTAB summary. In the navigation sidebar, click GTAB report (icon shown below).

Info

At the moment, it is only possible to add variants one by one to the GTAB summary. Please refer to the GTAB summary section for more details.

Page Errors

When we fail to load the gene data needed for search and gene filters to work, you won’t be able to apply any gene list filters or search by gene. All other information on the page will still be available. When we fail to load all variant data, we will show a full page error. In both cases try reloading the page.