16-31093399-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024006.6(VKORC1):c.196G>A(p.Val66Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,614,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00080 ( 0 hom., cov: 30)

Exomes 𝑓: 0.000083 ( 0 hom. )

Consequence

VKORC1
NM_024006.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:1

Conservation

PhyloP100: 2.83

Publications

46 publications found

Variant links:

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]

VKORC1 Gene-Disease associations (from GenCC):

vitamin K-dependent clotting factors, combined deficiency of, type 2
Inheritance: Unknown, AR Classification: MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
vitamin K-dependent clotting factors, combined deficiency of, type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

VKORC1 links:

ENSG00000255439 (HGNC:):

ENSG00000255439 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.017074674).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6 link	c.196G>A	p.Val66Met	missense_variant	Exon 2 of 3	ENST00000394975.3	NP_076869.1	Q9BQB6-1A0A0S2Z6I4
VKORC1	NM_001311311.2 link	c.196G>A	p.Val66Met	missense_variant	Exon 2 of 4		NP_001298240.1	Q9BQB6
VKORC1	NM_206824.3 link	c.173+1158G>A		intron_variant	Intron 1 of 1		NP_996560.1	Q9BQB6-3A0A0S2Z5X7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VKORC1	ENST00000394975.3 link	c.196G>A	p.Val66Met	missense_variant	Exon 2 of 3	1	NM_024006.6	ENSP00000378426.2		Q9BQB6-1
ENSG00000255439	ENST00000529564.1 link	c.196G>A	p.Val66Met	missense_variant	Exon 2 of 5	4		ENSP00000431371.1		E9PLN8

Frequencies

GnomAD3 genomes

AF:

0.000802

AC:

122

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000195

AC:

AN:

251118

AF XY:

0.0000958

show subpopulations

Gnomad AFR exome

AF:

0.00265

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000828

AC:

121

AN:

1461884

Hom.:

Cov.:

AF XY:

0.0000715

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00290

AC:

AN:

33480

American (AMR)

AF:

0.000157

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1112010

Other (OTH)

AF:

0.000232

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000801

AC:

122

AN:

152274

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74456

show subpopulations

African (AFR)

AF:

0.00279

AC:

116

AN:

41564

American (AMR)

AF:

0.000392

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5160

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000240

Hom.:

Bravo

AF:

0.000903

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000264

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Warfarin response

Pathogenic:1

Apr 12, 2018

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant has been previously reported in the literature in patients with warfarin resistance (PMID: 15630486). Functional studies demonstrate almost complete loss of activity for the p.Val66Met variant relative to wild type (PMID: 23039877). There are 70 reports of the variant as a heterozygous change in the population database, gnomAD, thus the variant is rare. The p.Val66Met residue is highly conserved among vertebrates, and the methionine substitution is predicted to be damaging by in silico models. Based on the combined evidence, the variant is classified as pathogenic. -

Vitamin K-dependent clotting factors, combined deficiency of, type 2

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Pathogenic

0.22

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.53

T;T;T

M_CAP

Pathogenic

0.47

MetaRNN

Benign

0.017

T;T;T

MetaSVM

Pathogenic

1.0

PhyloP100

2.8

PROVEAN

Benign

0.40

N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.14

T;D;D

Sift4G

Pathogenic

0.0

D;D;D

Vest4

0.54

MVP

0.92

ClinPred

0.075

GERP RS

6.2

PromoterAI

-0.0090

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.52

Mutation Taster

=6/94

disease causing (ClinVar)

(source)

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

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16-31093399-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over