rs2884737

Variant names:

• chr16-31094233-A-C
• rs2884737
• NM_024006.6:c.173+324T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_024006.6(VKORC1):​c.173+324T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,605,870 control chromosomes in the GnomAD database, including 46,667 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3338 hom., cov: 31)
  • Exomes 𝑓: 0.23 (43329 hom.)
• Consequence: VKORC1 NM_024006.6 intron
• Scores: Splicing: ADA: 0.00002433
• Clinical Significance: drug response reviewed by expert panel O:1
• Conservation: PhyloP100: -1.05
• Publications: 90 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.87194).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.256 is higher than 0.05.

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.173+324T>G		intron	N/A	NP_076869.1	Q9BQB6-1
	VKORC1	NM_001311311.2		c.173+324T>G		intron	N/A	NP_001298240.1
	VKORC1	NM_206824.3		c.173+324T>G		intron	N/A	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.173+324T>G		intron	N/A	ENSP00000378426.2	Q9BQB6-1
	ENSG00000255439	ENST00000529564.1	TSL:4	c.173+324T>G		intron	N/A	ENSP00000431371.1	E9PLN8
	VKORC1	ENST00000319788.11	TSL:1	c.173+324T>G		intron	N/A	ENSP00000326135.7	Q9BQB6-2

Frequencies

GnomAD3 genomes AF: 0.180 AC: 27235 AN: 151380 Hom.: 3338 Cov.: 31

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.251

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.334

Gnomad EAS AF: 0.00136

Gnomad SAS AF: 0.0865

Gnomad FIN AF: 0.224

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.242

GnomAD2 exomes AF: 0.192 AC: 46152 AN: 240676 AF XY: 0.195

Gnomad AFR exome AF: 0.0372

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.324

Gnomad EAS exome AF: 0.00101

Gnomad FIN exome AF: 0.214

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.240

GnomAD4 exome AF: 0.232 AC: 337783 AN: 1454372 Hom.: 43329 Cov.: 33 AF XY: 0.230 AC XY: 166226 AN XY: 722082

African (AFR) AF: 0.0425 AC: 1418 AN: 33382

American (AMR) AF: 0.141 AC: 6292 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 8436 AN: 25990

East Asian (EAS) AF: 0.000506 AC: 20 AN: 39512

South Asian (SAS) AF: 0.0988 AC: 8500 AN: 86058

European-Finnish (FIN) AF: 0.218 AC: 11374 AN: 52252

Middle Eastern (MID) AF: 0.407 AC: 2337 AN: 5748

European-Non Finnish (NFE) AF: 0.259 AC: 286112 AN: 1106800

Other (OTH) AF: 0.221 AC: 13294 AN: 60064

GnomAD4 genome AF: 0.180 AC: 27239 AN: 151498 Hom.: 3338 Cov.: 31 AF XY: 0.177 AC XY: 13099 AN XY: 74006

African (AFR) AF: 0.0448 AC: 1849 AN: 41272

American (AMR) AF: 0.196 AC: 2990 AN: 15230

Ashkenazi Jewish (ASJ) AF: 0.334 AC: 1160 AN: 3468

East Asian (EAS) AF: 0.00136 AC: 7 AN: 5142

South Asian (SAS) AF: 0.0874 AC: 418 AN: 4780

European-Finnish (FIN) AF: 0.224 AC: 2346 AN: 10494

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.260 AC: 17615 AN: 67826

Other (OTH) AF: 0.240 AC: 500 AN: 2084

Alfa AF: 0.250 Hom.: 15285

Bravo AF: 0.172

TwinsUK AF: 0.256 AC: 948

ALSPAC AF: 0.249 AC: 958

ESP6500AA AF: 0.0462 AC: 81

ESP6500EA AF: 0.277 AC: 1105

ExAC AF: 0.187 AC: 22028

Asia WGS AF: 0.0530 AC: 186 AN: 3478

EpiCase AF: 0.277

EpiControl AF: 0.282

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	-	warfarin response - Dosage (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.87	T
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.36
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0096	N
PhyloP100		-1.1
GERP RS		-3.9
PromoterAI		0.087	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
dbscSNV1_RF	Benign	0.0
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: rs2884737; hg19: chr16-31105554; COSMIC: COSV56231774; COSMIC: COSV56231774;