Genetic Variant WBP2:p.Thr216Ala (chr17-75847496-T-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_012478.4(WBP2):c.646A>G(p.Thr216Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

WBP2
NM_012478.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.50

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19477999).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
WBP2	NM_012478.4 link	c.646A>G	p.Thr216Ala	missense_variant	Exon 6 of 8	ENST00000254806.8	NP_036610.2
WBP2	NM_001348170.1 link	c.646A>G	p.Thr216Ala	missense_variant	Exon 7 of 9		NP_001335099.1
WBP2	NM_001330499.2 link	c.511A>G	p.Thr171Ala	missense_variant	Exon 5 of 7		NP_001317428.1
WBP2	XM_047435712.1 link	c.580A>G	p.Thr194Ala	missense_variant	Exon 6 of 8		XP_047291668.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WBP2	ENST00000254806.8 link	c.646A>G	p.Thr216Ala	missense_variant	Exon 6 of 8	1	NM_012478.4	ENSP00000254806.3		Q969T9-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1439478

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

714742

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 02, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.646A>G (p.T216A) alteration is located in exon 6 (coding exon 6) of the WBP2 gene. This alteration results from a A to G substitution at nucleotide position 646, causing the threonine (T) at amino acid position 216 to be replaced by an alanine (A). 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

0.18

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.032

T;T;T;T;.;.;.

Eigen

Benign

-0.0094

Eigen_PC

Benign

0.071

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.78

T;T;T;.;T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.19

T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.;.;L;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.46

N;.;.;.;.;N;.

REVEL

Benign

0.096

Sift

Benign

0.42

T;.;.;.;.;T;.

Sift4G

Benign

1.0

T;T;T;T;T;T;.

Polyphen

0.61

P;.;.;P;.;.;.

Vest4

0.61

MutPred

0.27

Loss of glycosylation at T216 (P = 6e-04);Loss of glycosylation at T216 (P = 6e-04);.;Loss of glycosylation at T216 (P = 6e-04);.;.;.;

MVP

0.56

MPC

0.39

ClinPred

0.66

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.55

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over