Clarification regarding the ClinVar annotation assigned to chr7:117188684 T-G

[Ananya-Saji]

Dear VEP Team,

We would like to seek clarification regarding the ClinVar annotation assigned to the following genomic variant:
Genomic Coordinates

Chromosome: 7
Position: 117188684
Reference Allele: T
Alternate Allele: G
dbSNP ID: rs73715573

For this locus, VEP reports consequences on two overlapping transcripts:

CFTR (NM_000492.4.1210-11T>G)
ClinVar Variation ID: 178713
ClinVar record: https://www.ncbi.nlm.nih.gov/clinvar/variation/178713/

CFTR-AS1
HGVS: n.222-6091A>C

Our understanding is that the ClinVar record (Variation ID 178713) corresponds to the CFTR intronic variant NM_000492.4.1210-11T>G. However, we do not find a corresponding ClinVar entry for the CFTR-AS1 ncRNA transcript annotation.

Could you please clarify:

1. Why is the same ClinVar ID being reported for the CFTR-AS1 transcript consequence?
2. Does VEP assign ClinVar annotations at the genomic variant level and subsequently propagate them to all overlapping transcript consequences?
3. Is there a way to distinguish transcript-specific ClinVar assertions from genomic variant-level ClinVar annotations in the VEP output?

Any clarification regarding the annotation strategy for overlapping coding and non-coding transcripts would be greatly appreciated.

Thank you for your assistance.

Regards,
Ananya

[likhitha-surapaneni]

Hi @Ananya-Saji ,

What is the command you are using to run VEP?

According to ClinVar, this variant overlaps both the genes: CFTR and CFTR-AS1 in GRCh38. Are you interested in testing this for GRCh37?

ClinVar chooses the accession number/HGVS expression for the name based on a precedence order. In case of more than one choice because of overlapping genes, HGVS for a transcript from the submitted gene is used.

Ensembl VEP assigns ClinVar annotations at a transcript level. Since this variant is overlapping both the genes, you may be seeing ClinVar annotations in the VEP output.

Hope this is helpful.