rs2359612

Positions:

• chr16-31092475-A-G
• chr16-31092475-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BA1

The NM_024006.6(VKORC1):​c.283+837T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.649 in 151,936 control chromosomes in the GnomAD database, including 33,452 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency: Genomes: 𝑓 0.65 (33452 hom., cov: 31)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: drug response reviewed by expert panel B:1 O:1
• Conservation: PhyloP100: -1.08

Genes affected

VKORC1 (HGNC:23663): (vitamin K epoxide reductase complex subunit 1) This gene encodes the catalytic subunit of the vitamin K epoxide reductase complex, which is responsible for the reduction of inactive vitamin K 2,3-epoxide to active vitamin K in the endoplasmic reticulum membrane. Vitamin K is a required co-factor for carboxylation of glutamic acid residues by vitamin K-dependent gamma-carboxylase in blood-clotting enzymes. Allelic variation in this gene is associated with vitamin k-dependent clotting factors combined deficiency of 2, and increased resistance or sensitivity to warfarin, an inhibitor of vitamin K epoxide reductase. Pseudogenes of this gene are located on chromosomes 1 and X. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-31092475-A-G is Benign according to our data. Variant chr16-31092475-A-G is described in ClinVar as [drug_response]. Clinvar id is 225975.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=1, drug_response=1}.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.283+837T>C		intron_variant		ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.367+308T>C		intron_variant			NP_001298240.1
VKORC1	NM_206824.3	c.174-1133T>C		intron_variant			NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.283+837T>C		intron_variant		1	NM_024006.6	ENSP00000378426	P1

Frequencies

GnomAD3 genomes AF: 0.649 AC: 98558 AN: 151818 Hom.: 33404 Cov.: 31

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.557

Gnomad AMR AF: 0.596

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.821

Gnomad FIN AF: 0.609

Gnomad MID AF: 0.478

Gnomad NFE AF: 0.622

Gnomad OTH AF: 0.587

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.649 AC: 98662 AN: 151936 Hom.: 33452 Cov.: 31 AF XY: 0.648 AC XY: 48120 AN XY: 74246

Gnomad4 AFR AF: 0.792

Gnomad4 AMR AF: 0.596

Gnomad4 ASJ AF: 0.493

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.821

Gnomad4 FIN AF: 0.609

Gnomad4 NFE AF: 0.622

Gnomad4 OTH AF: 0.589

Alfa AF: 0.613 Hom.: 43717

Bravo AF: 0.641

Asia WGS AF: 0.528 AC: 1834 AN: 3478

ClinVar

Significance: drug response

Submissions summary: Benign:1 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 13, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

warfarin response - Dosage Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 1B: Level 1B clinical annotations describe variant-drug combinations with a high level of evidence supporting the association but no variant-specific prescribing guidance in an annotated clinical guideline or FDA drug label. Level 1B clinical annotations must be supported by at least two independent publications. Drug-variant association: Dosage

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2359612; hg19: chr16-31103796;