16-31093393-G-A

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.202C>T(p.His68Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,614,156 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H68R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

VKORC1
NM_024006.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.71

Publications

6 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=0.06757164).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VKORC1	NM_024006.6 link	c.202C>T	p.His68Tyr	missense_variant	Exon 2 of 3	ENST00000394975.3	NP_076869.1	Q9BQB6-1A0A0S2Z6I4
VKORC1	NM_001311311.2 link	c.202C>T	p.His68Tyr	missense_variant	Exon 2 of 4		NP_001298240.1	Q9BQB6
VKORC1	NM_206824.3 link	c.173+1164C>T		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.202C>T	p.His68Tyr	missense_variant	Exon 2 of 3	1	NM_024006.6	ENSP00000378426.2		Q9BQB6-1
ENSG00000255439	ENST00000529564.1 link	c.202C>T	p.His68Tyr	missense_variant	Exon 2 of 5	4		ENSP00000431371.1		E9PLN8

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000471

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000358

AC:

AN:

251178

AF XY:

0.000317

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000832

Gnomad NFE exome

AF:

0.000590

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000283

AC:

414

AN:

1461880

Hom.:

Cov.:

AF XY:

0.000276

AC XY:

201

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000899

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000313

AC:

348

AN:

1112010

Other (OTH)

AF:

0.000248

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

108

135

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000276

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41568

American (AMR)

AF:

0.0000653

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000471

AC:

AN:

68004

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000316

Hom.:

Bravo

AF:

0.000219

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000469

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Benign

0.79

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.020

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.60

T;T;T

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.068

T;T;T

MetaSVM

Uncertain

0.086

PhyloP100

1.7

PROVEAN

Benign

1.1

N;N;N

REVEL

Benign

0.27

Sift

Benign

0.43

T;D;D

Sift4G

Uncertain

0.034

D;D;D

Vest4

0.41

MVP

0.86

ClinPred

0.076

GERP RS

5.2

PromoterAI

0.043

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.30

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

16-31093393-G-A

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