[ensembl-dev] ClinVar clinical significance in VEP

Will McLaren will.mclaren at globalgenecorp.com
Fri Jun 21 11:07:28 BST 2019

Hi list,

VEP reports clinical significance states for known variants in the CLIN_SIG
field. There is potential for these to be mis-assigned to input variants
due to the way the data are mapped and stored in Ensembl's database. This
is best illustrated by example:

rs2228671 (http://www.ensembl.org/Homo_sapiens/Variation/Explore?v=rs2228671
a SNV listed with four alleles (C/A/G/T). It has five ClinVar annotations
mapped to it (
with varying significance states. If your input to VEP matches any of the
three ALT alleles (A, G, or T) at this position, then the returned
CLIN_SIG field is a list of all of those states, since the ClinVar entries
are assigned at the variant level (rsID), rather than more precisely at the
allele level. Post-filtering your VEP results for pathogenic variants will
then match, regardless of whether your input ALT was a pathogenic (T) or
benign (A) allele at this position.

A good solution is to use VEP's custom annotation function along with the
VCF files made available by ClinVar (
https://www.ncbi.nlm.nih.gov/variation/docs/ClinVar_vcf_files/), something

vep [options] -custom clinvar_20190609.vcf.gz,clinvar,vcf,exact,,CLNSIG

which will give correct allele-specific clinical significance states in the
clinvar_CLNSIG field of the VEP output.

I haven't reported this as a bug for VEP as really it's a bug in the way
Ensembl stores the data.



## commands to reproduce:

# the A allele is pathogenic
$ vep -id "19 11100236 test1 C A" -cache -o stdout -no_head -pick -tab
-check_ex -fields CLIN_SIG,clinvar_CLNSIG -custom
benign,pathogenic       Pathogenic

# the T allele is benign
$ vep -id "19 11100236 test1 C T" -cache -o stdout -no_head -pick -tab
-check_ex -fields CLIN_SIG,clinvar_CLNSIG -custom
benign,pathogenic       Benign/Likely_benign

*William McLaren*
Senior Bioinformatics Scientist
Global Gene Corp
will.mclaren at globalgenecorp.com
The BIC, Wellcome Genome Campus, Hinxton, Cambridge CB10 1DR

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