rs2884737

Positions:

• chr16-31094233-A-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024006.6(VKORC1):​c.173+324T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,605,870 control chromosomes in the GnomAD database, including 46,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3338 hom., cov: 31)
  • Exomes 𝑓: 0.23 (43329 hom.)
• Consequence: VKORC1 NM_024006.6 intron
• Scores: Splicing: ADA: 0.00002433
• Clinical Significance: drug response reviewed by expert panel O:1
• Conservation: PhyloP100: -1.05

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.87194).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VKORC1	NM_024006.6	c.173+324T>G		intron_variant		ENST00000394975.3	NP_076869.1
VKORC1	NM_001311311.2	c.173+324T>G		intron_variant			NP_001298240.1
VKORC1	NM_206824.3	c.173+324T>G		intron_variant			NP_996560.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3	c.173+324T>G		intron_variant		1	NM_024006.6	ENSP00000378426	P1
	ENST00000624508.1	n.507A>C		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27235 AN: 151380 Hom.: 3338 Cov.: 31

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.0865

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.242

GnomAD3 exomes AF: 0.192 AC: 46152 AN: 240676 Hom.: 5712 AF XY: 0.195 AC XY: 25766 AN XY: 132048

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.324

Gnomad EAS exome AF: 0.00101

Gnomad SAS exome AF: 0.0953

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.240

GnomAD4 exome AF: 0.232 AC: 337783 AN: 1454372 Hom.: 43329 Cov.: 33 AF XY: 0.230 AC XY: 166226 AN XY: 722082

Gnomad4 AFR exome AF: 0.0425

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.325

Gnomad4 EAS exome AF: 0.000506

Gnomad4 SAS exome AF: 0.0988

Gnomad4 FIN exome AF: 0.218

Gnomad4 NFE exome AF: 0.259

Gnomad4 OTH exome AF: 0.221

GnomAD4 genome AF: 0.180 AC: 27239 AN: 151498 Hom.: 3338 Cov.: 31 AF XY: 0.177 AC XY: 13099 AN XY: 74006

Gnomad4 AFR AF: 0.0448

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.334

Gnomad4 EAS AF: 0.00136

Gnomad4 SAS AF: 0.0874

Gnomad4 FIN AF: 0.224

Gnomad4 NFE AF: 0.260

Gnomad4 OTH AF: 0.240

Alfa AF: 0.262 Hom.: 8662

Bravo AF: 0.172

TwinsUK AF: 0.256 AC: 948

ALSPAC AF: 0.249 AC: 958

ESP6500AA AF: 0.0462 AC: 81

ESP6500EA AF: 0.277 AC: 1105

ExAC AF: 0.187 AC: 22028

Asia WGS AF: 0.0530 AC: 186 AN: 3478

EpiCase AF: 0.277

EpiControl AF: 0.282

ClinVar

Significance: drug response

Submissions summary: Other:1

Revision: reviewed by expert panel

Submissions by phenotype

warfarin response - Dosage Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2A: Variants in Level 2A clinical annotations are found in PharmGKB’s Tier 1 Very Important Pharmacogenes (VIPs). These variants are in known pharmacogenes, implying causation of drug phenotype is more likely. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2A 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_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.36
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0096	N
MutationTaster	Benign	1.0	P;P;P;P;P;P
GERP RS		-3.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		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: rs2884737; hg19: chr16-31105554; COSMIC: COSV56231774; COSMIC: COSV56231774;