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rs2359612

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_StrongBA1

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

Scores

2

Clinical Significance

drug response reviewed by expert panel B:1O:1

Conservation

PhyloP100: -1.08
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 UniProt
VKORC1NM_024006.6 linkuse as main transcriptc.283+837T>C intron_variant ENST00000394975.3
VKORC1NM_001311311.2 linkuse as main transcriptc.367+308T>C intron_variant
VKORC1NM_206824.3 linkuse as main transcriptc.174-1133T>C intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VKORC1ENST00000394975.3 linkuse as main transcriptc.283+837T>C intron_variant 1 NM_024006.6 P1Q9BQB6-1

Frequencies

GnomAD3 genomes
AF:
0.649
AC:
98558
AN:
151818
Hom.:
33404
Cov.:
31
show subpopulations
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
show subpopulations
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:1Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxMar 13, 2018This 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 panelcurationPharmGKBMar 24, 2021PharmGKB 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs2359612; hg19: chr16-31103796; API