17-75847528-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012478.4(WBP2):c.614A>G(p.Glu205Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000693 in 1,442,150 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: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: WBP2 NM_012478.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.30

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]

ACMG classification

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=0.3576485).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
WBP2	NM_012478.4	c.614A>G	p.Glu205Gly	missense_variant	6/8	ENST00000254806.8
WBP2	NM_001348170.1	c.614A>G	p.Glu205Gly	missense_variant	7/9
WBP2	NM_001330499.2	c.479A>G	p.Glu160Gly	missense_variant	5/7
WBP2	XM_047435712.1	c.548A>G	p.Glu183Gly	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
WBP2	ENST00000254806.8	c.614A>G	p.Glu205Gly	missense_variant	6/8	1	NM_012478.4	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1442150 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 716034

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: 9.08e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 14, 2023

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 205 of the WBP2 protein (p.Glu205Gly). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt WBP2 protein function. This variant has not been reported in the literature in individuals affected with WBP2-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.024	T;T;T;T;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.75	T;D;T;.;T;T;D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.9	L;.;.;L;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.19	N;.;.;.;.;N;.
REVEL	Benign	0.23
Sift	Benign	0.19	T;.;.;.;.;T;.
Sift4G	Benign	0.33	T;T;T;T;T;T;.
Polyphen		1.0	D;.;.;D;.;.;.
Vest4		0.65
MutPred		0.44		Loss of glycosylation at P203 (P = 0.1062);Loss of glycosylation at P203 (P = 0.1062);.;Loss of glycosylation at P203 (P = 0.1062);.;.;.;
MVP		0.77
MPC		0.48
ClinPred		0.77	D
GERP RS		3.9
Varity_R		0.14
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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.

Other links and lift over

hg19: chr17-73843609;