chr16-31094694-C-T

Variant names:

• chr16-31094694-C-T
• rs55894764
• NM_024006.6:c.36G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Moderate BP6_Moderate BP7 BS1 BS2

The NM_024006.6(VKORC1):​c.36G>A​(p.Arg12Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,608,310 control chromosomes in the GnomAD database, including 230 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. R12R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (32 hom., cov: 32)
  • Exomes 𝑓: 0.012 (198 hom.)
• Consequence: VKORC1 NM_024006.6 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.38
• Publications: 11 publications found

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255439 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 16-31094694-C-T is Benign according to our data. Variant chr16-31094694-C-T is described in ClinVar as Benign. ClinVar VariationId is 318977.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0118 (17223/1455944) while in subpopulation AMR AF = 0.0164 (729/44336). AF 95% confidence interval is 0.0155. There are 198 homozygotes in GnomAdExome4. There are 8352 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 32 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024006.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	NM_024006.6	MANE Select	c.36G>A	p.Arg12Arg	synonymous	Exon 1 of 3	NP_076869.1	Q9BQB6-1
	VKORC1	NM_001311311.2		c.36G>A	p.Arg12Arg	synonymous	Exon 1 of 4	NP_001298240.1
	VKORC1	NM_206824.3		c.36G>A	p.Arg12Arg	synonymous	Exon 1 of 2	NP_996560.1	Q9BQB6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.36G>A	p.Arg12Arg	synonymous	Exon 1 of 3	ENSP00000378426.2	Q9BQB6-1
	ENSG00000255439	ENST00000529564.1	TSL:4	c.36G>A	p.Arg12Arg	synonymous	Exon 1 of 5	ENSP00000431371.1	E9PLN8
	VKORC1	ENST00000319788.11	TSL:1	c.36G>A	p.Arg12Arg	synonymous	Exon 1 of 4	ENSP00000326135.7	Q9BQB6-2

Frequencies

GnomAD3 genomes AF: 0.0131 AC: 1990 AN: 152248 Hom.: 32 Cov.: 32

Gnomad AFR AF: 0.00229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.0750

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0124

GnomAD2 exomes AF: 0.0151 AC: 3528 AN: 233556 AF XY: 0.0144

Gnomad AFR exome AF: 0.00210

Gnomad AMR exome AF: 0.0158

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.0000559

Gnomad FIN exome AF: 0.0735

Gnomad NFE exome AF: 0.0117

Gnomad OTH exome AF: 0.0230

GnomAD4 exome AF: 0.0118 AC: 17223 AN: 1455944 Hom.: 198 Cov.: 32 AF XY: 0.0115 AC XY: 8352 AN XY: 724318

African (AFR) AF: 0.00120 AC: 40 AN: 33450

American (AMR) AF: 0.0164 AC: 729 AN: 44336

Ashkenazi Jewish (ASJ) AF: 0.0224 AC: 583 AN: 26058

East Asian (EAS) AF: 0.00 AC: 0 AN: 39604

South Asian (SAS) AF: 0.00171 AC: 147 AN: 85900

European-Finnish (FIN) AF: 0.0695 AC: 3457 AN: 49744

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5752

European-Non Finnish (NFE) AF: 0.0104 AC: 11538 AN: 1110922

Other (OTH) AF: 0.0120 AC: 721 AN: 60178

GnomAD4 genome AF: 0.0131 AC: 1991 AN: 152366 Hom.: 32 Cov.: 32 AF XY: 0.0154 AC XY: 1150 AN XY: 74510

African (AFR) AF: 0.00228 AC: 95 AN: 41588

American (AMR) AF: 0.0154 AC: 236 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 73 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4832

European-Finnish (FIN) AF: 0.0750 AC: 797 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0111 AC: 755 AN: 68044

Other (OTH) AF: 0.0123 AC: 26 AN: 2116

Alfa AF: 0.00964 Hom.: 6

Bravo AF: 0.00914

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Vitamin K-dependent clotting factors, combined deficiency of, type 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.94
PhyloP100		1.4
PromoterAI		0.032	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs55894764; hg19: chr16-31106015;