chr16-31093126-A-G

Variant names:

• chr16-31093126-A-G
• rs17886199
• NM_024006.6:c.283+186T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_024006.6(VKORC1):​c.283+186T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 152,186 control chromosomes in the GnomAD database, including 48 homozygotes. 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: 𝑓 0.013 (48 hom., cov: 31)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.155
• 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: 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0128 (1947/152186) while in subpopulation AFR AF = 0.0447 (1854/41516). AF 95% confidence interval is 0.043. There are 48 homozygotes in GnomAd4. There are 894 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 48 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	NM_024006.6	MANE Select	c.283+186T>C		intron	N/A	NP_076869.1
	VKORC1	NM_001311311.2		c.283+186T>C		intron	N/A	NP_001298240.1
	VKORC1	NM_206824.3		c.173+1431T>C		intron	N/A	NP_996560.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VKORC1	ENST00000394975.3	TSL:1 MANE Select	c.283+186T>C		intron	N/A	ENSP00000378426.2
	ENSG00000255439	ENST00000529564.1	TSL:4	c.283+186T>C		intron	N/A	ENSP00000431371.1
	VKORC1	ENST00000319788.11	TSL:1	c.283+186T>C		intron	N/A	ENSP00000326135.7

Frequencies

GnomAD3 genomes AF: 0.0128 AC: 1942 AN: 152068 Hom.: 48 Cov.: 31

Gnomad AFR AF: 0.0446

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00719

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0128 AC: 1947 AN: 152186 Hom.: 48 Cov.: 31 AF XY: 0.0120 AC XY: 894 AN XY: 74420

African (AFR) AF: 0.0447 AC: 1854 AN: 41516

American (AMR) AF: 0.00373 AC: 57 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68004

Other (OTH) AF: 0.00712 AC: 15 AN: 2108

Alfa AF: 0.00579 Hom.: 30

Bravo AF: 0.0146

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.7
DANN	Benign	0.69
PhyloP100		-0.15
PromoterAI		0.0017	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs17886199; hg19: chr16-31104447;