chr16-31092475-A-T

Variant names:

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

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-2 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -2 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Strong

The NM_024006.6(VKORC1):c.283+837T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: VKORC1 NM_024006.6 intron
• Clinical Significance: Not reported in ClinVar
• 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: Likely_benign. The variant received -2 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	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).

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>A	intron	Intron 2 of 2	Prot: NP_076869.1 UniProt:
	VKORC1 NM_001311311.2		c.367+308T>A	intron	Intron 3 of 3	Prot: NP_001298240.1
	VKORC1 NM_206824.3		c.174-1133T>A	intron	Intron 1 of 1	Prot: NP_996560.1 UniProt:

VKORC1 NM_024006.6

MANE Select

HGVSc / HGVSpc.283+837T>A

Exon rankIntron 2 of 2

intron

Prot: NP_076869.1UniProt: A0A0S2Z6I4Q9BQB6-1

VKORC1 NM_001311311.2

HGVSc / HGVSpc.367+308T>A

Exon rankIntron 3 of 3

intron

Prot: NP_001298240.1

VKORC1 NM_206824.3

HGVSc / HGVSpc.174-1133T>A

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>A	intron	Intron 2 of 2	Prot: ENSP00000378426.2 UniProt:
	ENSG00000255439 ENST00000529564.1	TSL:4	c.283+837T>A	intron	Intron 2 of 4	Prot: ENSP00000431371.1 UniProt:
	VKORC1 ENST00000319788.11	TSL:1	c.365+308T>A	intron	Intron 3 of 3	Prot: ENSP00000326135.7 UniProt:

VKORC1 ENST00000394975.3

TSL:1MANE Select

HGVSc / HGVSpc.283+837T>A

Exon rankIntron 2 of 2

intron

Prot: ENSP00000378426.2UniProt: Q9BQB6-1

ENSG00000255439 ENST00000529564.1

TSL:4

HGVSc / HGVSpc.283+837T>A

Exon rankIntron 2 of 4

intron

Prot: ENSP00000431371.1UniProt: E9PLN8

VKORC1 ENST00000319788.11

TSL:1

HGVSc / HGVSpc.365+308T>A

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31

Showing 2 sources

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

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.0
DANN	Benign	0.82
GPN-Star LLR	N/A	0.49
GPN-Star score	N/A	-0.49
PhyloP100	Benign	-1.1

Showing 7 of 7 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.020	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