Germline CNV Calling ASCN (WGS)

The Germline WGS CNV caller (with Allele-Specific CN support) leverages depth of coverage and B-allele frequencies (BAFs) to detect germline copy number aberrations and regions with absence of heterozygosity (AOH).

The caller requires in input the sample to analyze and a catalog of population SNPs (used to estimate the B-allele frequencies across the genome). The output file is a VCF file. Several components of other germline CNV callers are reused, such as target and b-allele counts estimation, bias correction, normalization and segmentation. More details on the sample model selection are available in the ASCN calling section. See Output Files for more details on output files.

When enabled (default true), the caller can output an additional VCF with calls at resolutions compatible with cytogenetics technologies (e.g., ≥ 1 Mb, or whole-arm/whole-chromosome calls) For more information, see Cytogenetics modality.

Germline WGS CNV Calling (ASCN) Options

You can use the following command-line options:

Option
Description

--fastq-file1,--fastq-file2,--bam-input, --cram-input

Specify an input file.

--cnv-population-b-allele-vcf

Specify a population SNP catalog. For more information on specifying b-allele loci, see Specification of B-Allele Loci.

--enable-cnv

Enable or disable CNV processing. Set to true to enable CNV processing.

--enable-map-align

Enables the mapper and aligner module.

--output-directory

Output directory where all results are stored.

--output-file-prefix

Output file prefix that will be prepended to all result file names.

--ref-dir

The DRAGEN reference genome hashtable directory.

--sample-sex

If known, specify the sex of the sample. If the sample sex is not specified, the caller attempts to estimate the sample sex from alignments.

--cnv-enable-mosaic-calling

Enable MOSAIC-calling mode (default true). For more information, see MOSAIC-Calling Mode.

--cnv-enable-cyto-output

Enable Cytogenetics-compatible output (default true). For more information, see Cytogenetics Modality.

--cnv-enable-legacy-vcf-format

Use VCF v4.2 for CNV VCF output (default false).

--cnv-enable-self-normalization

Use self-normalization to normalize input sample.

Example command lines

The following is an example command line:

dragen \
-r <HASHTABLE> \
--output-directory <OUTPUT> \
--output-file-prefix <SAMPLE> \
--enable-map-align false \
--enable-cnv true \
--bam-input <BAM> \
--cnv-enable-self-normalization true \
--cnv-population-b-allele-vcf <SNV_POP_VCF> \
--sample-sex <SEX>

Differences with respect to Germline WGS CNV (Depth-only)

The Germline WGS ASCN caller differs from the depth-only caller in various respects:

  • Whereas both the depth-only caller and the ASCN caller make use of a depth of coverage profile, the ASCN caller (but not the depth-only caller) additionally makes use of allelic read counts at sites along the genome provided through a population SNP catalog.

  • The ASCN caller segments both profiles (depth and BAF), then integrates their results. The depth-only caller only segments the depth profile.

  • The ASCN caller estimates the most likely diploid coverage for the input sample using both profiles (depth and BAF), while the depth-only caller has only the depth profile at its disposal.

  • The ASCN caller can also detect AOH/LOH regions and mosaic alterations, while the depth-only caller is limited to DEL and DUP regions.

Briefly, the following table summarizes the above differences:

Feature
Depth-only caller
ASCN caller

Coverage Depth Profile

B-Allele Frequency Profile

Coverage Depth Segmentation

B-Allele Frequency Segmentation

DEL/DUP Detection

Whole-arm/-chromosome Aneuploidy Detection

✓ (Requires Cytogenetics Modality)

Whole-Genome Trisomy Detection

Minor-Allele Copy-Number Estimation

AOH/LOH Detection

Mosaic Alterations Detection

Limitations

The following features available in the non-ASCN germline caller are not yet supported:

  • Pedigree mode

  • Exome support

  • Star-Allele caller integration

  • Segmental Duplications extension

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