7-49912057-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_198570.5(VWC2):c.850G>A(p.Ala284Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000304 in 1,613,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00031 ( 0 hom. )

Consequence

VWC2
NM_198570.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.62

Publications

2 publications found

Variant links:

Genes affected

VWC2 (HGNC:30200): (von Willebrand factor C domain containing 2) This gene encodes a secreted bone morphogenic protein antagonist. The encoded protein is possibly involved in neural function and development and may have a role in cell adhesion.[provided by RefSeq, Oct 2009]

VWC2 links:

ZPBP (HGNC:15662): (zona pellucida binding protein) ZPBP is one of several proteins that are thought to participate in secondary binding between acrosome-reacted sperm and the egg-specific extracellular matrix, the zona pellucida (McLeskey et al., 1998 [PubMed 9378618]).[supplied by OMIM, Aug 2008]

ZPBP Gene-Disease associations (from GenCC):

spermatogenic failure 66
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ZPBP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008113176).

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VWC2	NM_198570.5 link	c.850G>A	p.Ala284Thr	missense_variant	Exon 4 of 4	ENST00000340652.5	NP_940972.2	Q2TAL6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
VWC2	ENST00000340652.5 link	c.850G>A	p.Ala284Thr	missense_variant	Exon 4 of 4	1	NM_198570.5	ENSP00000341819.3	Q2TAL6
ZPBP	ENST00000465922.1 link	n.412-10842C>T		intron_variant	Intron 1 of 2	4
ZPBP	ENST00000491129.5 link	n.419-10842C>T		intron_variant	Intron 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

151932

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000947

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000219

AC:

AN:

251208

AF XY:

0.000236

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00149

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000238

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000313

AC:

457

AN:

1461686

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

222

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.000119

AC:

AN:

33480

American (AMR)

AF:

0.0000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00149

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.000345

AC:

384

AN:

1111886

Other (OTH)

AF:

0.000215

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000224

AC:

AN:

151932

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74184

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41342

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000208

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.0000947

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000353

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000294

Hom.:

Bravo

AF:

0.000193

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000231

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.850G>A (p.A284T) alteration is located in exon 4 (coding exon 3) of the VWC2 gene. This alteration results from a G to A substitution at nucleotide position 850, causing the alanine (A) at amino acid position 284 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.0011

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.60

M_CAP

Benign

0.0033

MetaRNN

Benign

0.0081

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.1

PhyloP100

1.6

PrimateAI

Benign

0.46

PROVEAN

Benign

0.31

REVEL

Benign

0.058

Sift

Benign

0.79

Sift4G

Benign

1.0

Polyphen

0.068

Vest4

0.022

MVP

0.082

MPC

0.97

ClinPred

0.013

GERP RS

3.8

Varity_R

0.037

gMVP

0.55

Mutation Taster

=95/5

polymorphism

(source)

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

Publications

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7-49912057-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over