chr16-31092475-A-G

Variant names:

• chr16-31092475-A-G
• rs2359612
• NM_024006.6:c.283+837T>C

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -12 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_Strong

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 cumulative frequency of 0.649 (AC=98,662) in the gnomAD database across 151,936 control chromosomes, including 33,452 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.8. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★★).

• Frequency: Genomes: 𝑓 0.65 (33452 hom., cov: 31)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: drug response reviewed by expert panel B:2 O:1
• Conservation: PhyloP100: -1.08
• Publications: 12 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):

• coumarin resistance

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• vitamin K-dependent clotting factors, combined deficiency of, type 2

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255439 (HGNC:):

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Benign. The variant received -12 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.7999 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VKORC1 NM_024006.6	MANE Select	c.283+837T>C	intron	Intron 2 of 2	Prot: NP_076869.1 UniProt:
	VKORC1 NM_001311311.2		c.367+308T>C	intron	Intron 3 of 3	Prot: NP_001298240.1
	VKORC1 NM_206824.3		c.174-1133T>C	intron	Intron 1 of 1	Prot: NP_996560.1 UniProt:

VKORC1 NM_024006.6

MANE Select

HGVSc / HGVSpc.283+837T>C

Exon rankIntron 2 of 2

intron

Prot: NP_076869.1UniProt: A0A0S2Z6I4Q9BQB6-1

VKORC1 NM_001311311.2

HGVSc / HGVSpc.367+308T>C

Exon rankIntron 3 of 3

intron

Prot: NP_001298240.1

VKORC1 NM_206824.3

HGVSc / HGVSpc.174-1133T>C

Exon rankIntron 1 of 1

intron

Prot: NP_996560.1UniProt: Q9BQB6-3A0A0S2Z5X7

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VKORC1 ENST00000394975.3	TSL:1MANE Select	c.283+837T>C	intron	Intron 2 of 2	Prot: ENSP00000378426.2 UniProt:
	ENSG00000255439 ENST00000529564.1	TSL:4	c.283+837T>C	intron	Intron 2 of 4	Prot: ENSP00000431371.1 UniProt:
	VKORC1 ENST00000319788.11	TSL:1	c.365+308T>C	intron	Intron 3 of 3	Prot: ENSP00000326135.7 UniProt:

VKORC1 ENST00000394975.3

TSL:1MANE Select

HGVSc / HGVSpc.283+837T>C

Exon rankIntron 2 of 2

intron

Prot: ENSP00000378426.2UniProt: Q9BQB6-1

ENSG00000255439 ENST00000529564.1

TSL:4

HGVSc / HGVSpc.283+837T>C

Exon rankIntron 2 of 4

intron

Prot: ENSP00000431371.1UniProt: E9PLN8

VKORC1 ENST00000319788.11

TSL:1

HGVSc / HGVSpc.365+308T>C

Exon rankIntron 3 of 3

intron

Prot: ENSP00000326135.7UniProt: Q9BQB6-2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.649	AC:98558	Hom:33404	AN:151818	Cov:31
GnomAD4 genome	AF: 0.649	AC:98662	Hom:33452	AN:151936	Cov:31
TOPMed (Bravo)	AF: 0.641	AC:169639	Hom:57045	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.618	AC:333291	Hom:105595	AN:539518	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.605	AC:1417	Hom:442	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0913	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.610	AC:183	Hom:	AN:300	Cov:
GenomeAsia100K	AF: 0.528	AC:1834	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0740	AC:533	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.511	AC:90	Hom:	AN:176	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0941	AC:11321	Hom:536	AN:120248	Cov:
Turkish Variome	AF: 0.527	AC:814	Hom:219	AN:1546	Cov:
UK10K	AF: 0.631	AC:4770	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0923	AC:827	Hom:45	AN:8960	Cov:

Showing 14 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	-	warfarin response - Dosage (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.64
GPN-Star LLR	N/A	2.7
GPN-Star score	N/A	-1.1
Mutation Taster	N/A	100/0	polymorphism (auto)
PhyloP100	Benign	-1.1

Showing 8 of 8 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2359612;

hg19: chr16-31103796;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar