17-75846958-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_012478.4(WBP2):c.682G>A(p.Ala228Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,613,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

WBP2
NM_012478.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.43

Variant links:

Genes affected

WBP2 (HGNC:12738): (WW domain binding protein 2) The globular WW domain is composed of 38 to 40 semiconserved amino acids shared by proteins of diverse functions including structural, regulatory, and signaling proteins. The domain is involved in mediating protein-protein interactions through the binding of polyproline ligands. This gene encodes a WW domain binding protein that is a transcriptional coactivator of estrogen receptor alpha and progesterone receptor. Defects in this gene have been associated with hearing impairment. [provided by RefSeq, Jan 2017]

WBP2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37343603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
WBP2	NM_012478.4 link	c.682G>A	p.Ala228Thr	missense_variant	Exon 7 of 8	ENST00000254806.8	NP_036610.2
WBP2	NM_001348170.1 link	c.682G>A	p.Ala228Thr	missense_variant	Exon 8 of 9		NP_001335099.1
WBP2	NM_001330499.2 link	c.547G>A	p.Ala183Thr	missense_variant	Exon 6 of 7		NP_001317428.1
WBP2	XM_047435712.1 link	c.616G>A	p.Ala206Thr	missense_variant	Exon 7 of 8		XP_047291668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WBP2	ENST00000254806.8 link	c.682G>A	p.Ala228Thr	missense_variant	Exon 7 of 8	1	NM_012478.4	ENSP00000254806.3		Q969T9-1

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251120

Hom.:

AF XY:

0.0000663

AC XY:

AN XY:

135814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000128

AC:

187

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000160

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74302

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000491

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Oct 22, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with threonine at codon 228 of the WBP2 protein (p.Ala228Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs367581512, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with WBP2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.054

T;T;T;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.92

D;D;.;D;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.37

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.3

M;.;M;.;.

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.0

N;.;.;.;N

REVEL

Benign

0.11

Sift

Uncertain

0.017

D;.;.;.;D

Sift4G

Benign

0.18

T;T;T;T;T

Polyphen

1.0

D;.;D;.;.

Vest4

0.56

MVP

0.73

MPC

0.31

ClinPred

0.22

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.26

gMVP

0.54

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over