Clinical significance explanation

Question

[abedkurdi10]

Hi all, I have a question about CLNSIG field in clinvar database:

5       73981270        rs820878        T       C       1777.96 PASS    AC=2;AF=1;AN=2;DP=68;Dels=0;FS=0;HRun=0;HaplotypeScore=9.785;MQ=48.79;MQ0=0;QD=26.15;SB=-1169.48;TI=NM_000521;GI=HEXB;FC=Missense_L62S;EXON;CLNSIG=5,2;CLNDBN=Sandhoff_disease\x2c_infantile_type,not_specified;CLNORIGIN=1,1   GT:AD:DP:GQ:PL:VF:GQX   1/1:0,68:68:99:1811,132,0:1:99
5       73992881        rs10805890      A       G       2934.35 PASS    AC=1;AF=0.5;AN=2;BaseQRankSum=2.658;DP=228;Dels=0;FS=0;HRun=1;HaplotypeScore=15.9174;MQ=49.18;MQ0=0;MQRankSum=-2.022;QD=12.87;ReadPosRankSum=0.741;SB=-2190.96;TI=NM_000521;GI=HEXB;FC=Missense_I207V;EXON;CLNSIG=255|2;CLNDBN=not_specified|HEXB_POLYMORPHISM;CLNORIGIN=1      GT:AD:DP:GQ:PL:VF:GQX   0/1:87,140:228:99:2964,0,1723:0.617:99
5       89979691        rs41303352      A       G       837.32  PASS    AC=1;AF=0.5;AN=2;BaseQRankSum=-0.06;DP=112;Dels=0;FS=0;HRun=0;HaplotypeScore=5.5655;MQ=40.13;MQ0=0;MQRankSum=0.042;QD=7.48;ReadPosRankSum=-2.537;SB=-599.97;TI=NR_003149,NM_032119;GI=GPR98,GPR98;FC=Silent,Missense_N1985D;EXON;CLNSIG=0|3,255;CLNDBN=not_provided|not_specified,not_specified;CLNORIGIN=1,1   GT:AD:DP:GQ:PL:VF:GQX   0/1:69,43:112:99:867,0,1384:0.384:99

1. what does CLNSIG=5,2 mean ? does it mean 5 or 2 ?
2. what does CLNSIG=255|2 mean ?
3. what does CLNSIG=0|3,255 mean ?

I appreciate any helpful explanation. Thank you.

[agata88]

I think you have explanation in vcf header lines. Paste it here. Best, Agata

[abedkurdi10]

> ##INFO=<ID=CLNSIG,Number=.,Type=String,Description="Variant Clinical Significance, 0 - Uncertain significance, 1 - not provided, 2 -
> Benign, 3 - Likely benign, 4 - Likely pathogenic, 5 - Pathogenic, 6 -
> drug response, 7 - histocompatibility, 255 - other">
> ##INFO=<ID=CLNDBN,Number=.,Type=String,Description="Variant disease name">
> ##INFO=<ID=CLNORIGIN,Number=.,Type=String,Description="Allele Origin. One or more of the following values may be added: 0 - unknown; 1 -
> germline; 2 - somatic; 4 - inherited; 8 - paternal; 16 - maternal; 32
> - de-novo; 64 - biparental; 128 - uniparental; 256 - not-tested; 512 - tested-inconclusive; 1073741824 - other">

[agata88]

So, everything is explained above. Here is the link for clinvar for first rs820878.

https://www.ncbi.nlm.nih.gov/clinvar?term=rs820878%5BVariant%20ID%5D

You can always see the explanation in this database.

[Zaag]

So CLNSIG=5,2 would mean it is both benign and pathogenic?

[agata88]

Yes I think so. But here is one thing that I would be happy to read about from somebody more experience than me in this area - here in vcf file the variant T/C is annotated as rs820878. But Clinvar and dbSNP show C/T change - with pathogenic allele T. This T allele is in hg19 and hg38 genome reference, so how can it be pathogenic? What am I missing here?

In my opinion variant T/C is not the one in rs820878, it has the same localization but it's not rs820878, so wrong annotation.

https://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?searchType=adhoc_search&type=rs&rs=rs820878

[abedkurdi10]

the explanation for many values for one variant is not clear, even in here: https://www.ncbi.nlm.nih.gov/clinvar/docs/clinsig/