Calculation variant frequencies for copy number events for a cohort

Question

[barslmn]

Hi,

I have CNV calls of a cohort of patients in both individual VCF and GFF files.

I want to get to the rare ones, so I want to calculate frequencies for the variants within the cohort.

I found this plink approach but wondering if there is any other method or tool that can calculate frequencies directly using the VCF or GFF files?

GFF example

##gff-version 3
chr1    DRAGEN  CNV     925732  945653  3       .       .       Alt=DUP;LinearCopyRatio=1.23097;CopyNumber=3;Genotype=./1;Qual=3;Filter=cnvQual;Start=925731;Stop=945653;Length=19922;BinCount=30;ImproperPairsCount=8,7;color=#DDDDDD;
chr1    DRAGEN  CNV     1468885 1478297 11      .       .       Alt=DEL;LinearCopyRatio=0.677751;CopyNumber=1;Genotype=0/1;Qual=11;Filter=cnvQual;Start=1468884;Stop=1478297;Length=9413;BinCount=4;ImproperPairsCount=1,10;color=#DDDDDD;
chr1    DRAGEN  CNV     2073665 2073797 52      .       .       Alt=DEL;LinearCopyRatio=8.51417e-10;CopyNumber=0;Genotype=1/1;Qual=52;Filter=PASS;Start=2073664;Stop=2073797;Length=133;BinCount=1;ImproperPairsCount=0,0;color=#0000FF;
chr1    DRAGEN  CNV     2321254 2336850 51      .       .       Alt=DUP;LinearCopyRatio=1.43867;CopyNumber=3;Genotype=.1;Qual=51;Filter=PASS;Start=2321253;Stop=2336850;Length=15597;BinCount=8;ImproperPairsCount=4,4;color=#FF0000;
chr1    DRAGEN  CNV     5952701 5986327 4       .       .       Alt=DUP;LinearCopyRatio=1.23552;CopyNumber=3;Genotype=.1;Qual=4;Filter=cnvQual;Start=5952700;Stop=5986327;Length=33627;BinCount=12;ImproperPairsCount=32,8;color=#DDDDDD;

VCF example

#CHROM  POS     ID      REF     ALT     QUAL    FILTER  INFO    FORMAT  ID_001
chr1    925731  DRAGEN:GAIN:chr1:925732-945653  N       <DUP>   3       cnvQual SVLEN=19922;SVTYPE=CNV;END=945653;REFLEN=19922  GT:SM:CN:BC:PE  ./1:1.23097:3:30:8,7
chr1    1468884 DRAGEN:LOSS:chr1:1468885-1478297        N       <DEL>   11      cnvQual SVLEN=-9413;SVTYPE=CNV;END=1478297;REFLEN=9413  GT:SM:CN:BC:PE  0/1:0.677751:1:4:1,10
chr1    2073664 DRAGEN:LOSS:chr1:2073665-2073797        N       <DEL>   52      PASS    SVLEN=-133;SVTYPE=CNV;END=2073797;REFLEN=133    GT:SM:CN:BC:PE  1/1:8.51417e-10:0:1:0,0
chr1    2321253 DRAGEN:GAIN:chr1:2321254-2336850        N       <DUP>   51      PASS    SVLEN=15597;SVTYPE=CNV;END=2336850;REFLEN=15597 GT:SM:CN:BC:PE  ./1:1.43867:3:8:4,4

Answer 1

[LChart]

If you use the multisample CNV caller from DRAGEN, you'll be able to calculate AC/AF/AN directly in the VCF, as copy numbers will be jointly segmented across samples. As it is, you should find that a small fraction of the variants exactly match, as the breakpoints will be ragged. As such you're probably best off with gff -> bed -> bedtools multiinter (or other interval arithmetic you choose) to establish "consensus" copy number events and a list of their carriers. Also dup/del need to be processed separately, with deletions retaining their genotypes (since one can me missing 1 or 2 copies).

Good luck!

[barslmn]

Thanks for your directions. One thing I notice when I look back on documentation is that joint CNV calling examples are given as trios. That's why I didn't try to use the joint calling. I will give it shot and see if it works without the pedigree file.