chr16-31093188-C-A

Variant names:

• chr16-31093188-C-A
• rs8050894
• NM_024006.6:c.283+124G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001311311.2(VKORC1):​c.283+124G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000114 in 878,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: VKORC1 NM_001311311.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.576
• Publications: 115 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: 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

ENSG00000255439 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001311311.2. 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.283+124G>T		intron	N/A	NP_076869.1
	VKORC1	NM_001311311.2		c.283+124G>T		intron	N/A	NP_001298240.1
	VKORC1	NM_206824.3		c.173+1369G>T		intron	N/A	NP_996560.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.283+124G>T		intron	N/A	ENSP00000378426.2
	ENSG00000255439	ENST00000529564.1	TSL:4	c.283+124G>T		intron	N/A	ENSP00000431371.1
	VKORC1	ENST00000319788.11	TSL:1	c.283+124G>T		intron	N/A	ENSP00000326135.7

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.0000114 AC: 10 AN: 878658 Hom.: 0 AF XY: 0.0000134 AC XY: 6 AN XY: 447674

African (AFR) AF: 0.00 AC: 0 AN: 22738

American (AMR) AF: 0.00 AC: 0 AN: 34222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20064

East Asian (EAS) AF: 0.0000294 AC: 1 AN: 34044

South Asian (SAS) AF: 0.00 AC: 0 AN: 64806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33088

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2982

European-Non Finnish (NFE) AF: 0.0000144 AC: 9 AN: 625692

Other (OTH) AF: 0.00 AC: 0 AN: 41022

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 6711

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.70
DANN	Benign	0.73
PhyloP100		-0.58
PromoterAI		-0.014	Neutral

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

Other links and lift over

dbSNP: rs8050894; hg19: chr16-31104509;