17-75846769-G-C

Variant names:

• chr17-75846769-G-C
• rs2143913584
• NM_012478.4:c.751C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012478.4(WBP2):​c.751C>G​(p.Pro251Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,397,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P251T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: WBP2 NM_012478.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.27
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• hearing loss, autosomal recessive 107

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30542457).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012478.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WBP2	NM_012478.4	MANE Select	c.751C>G	p.Pro251Ala	missense	Exon 8 of 8	NP_036610.2
	WBP2	NM_001348170.1		c.751C>G	p.Pro251Ala	missense	Exon 9 of 9	NP_001335099.1	Q969T9-1
	WBP2	NM_001330499.2		c.616C>G	p.Pro206Ala	missense	Exon 7 of 7	NP_001317428.1	Q969T9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	WBP2	ENST00000254806.8	TSL:1 MANE Select	c.751C>G	p.Pro251Ala	missense	Exon 8 of 8	ENSP00000254806.3	Q969T9-1
	WBP2	ENST00000591399.5	TSL:5	c.751C>G	p.Pro251Ala	missense	Exon 9 of 9	ENSP00000467579.1	Q969T9-1
	WBP2	ENST00000590221.5	TSL:3	c.739C>G	p.Pro247Ala	missense	Exon 8 of 8	ENSP00000466450.1	K7EMC9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1397030 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688254

African (AFR) AF: 0.00 AC: 0 AN: 31874

American (AMR) AF: 0.00 AC: 0 AN: 36154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22790

East Asian (EAS) AF: 0.00 AC: 0 AN: 37758

South Asian (SAS) AF: 0.00 AC: 0 AN: 76306

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50012

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5556

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078796

Other (OTH) AF: 0.00 AC: 0 AN: 57784

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.067	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.15
Sift	Uncertain	0.018	D
Sift4G	Benign	0.36	T
Polyphen		1.0	D
Vest4		0.21
MutPred		0.25		Loss of glycosylation at P251 (P = 0.0012)
MVP		0.78
MPC		0.74
ClinPred		0.94	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.45

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

Other links and lift over

dbSNP: rs2143913584; hg19: chr17-73842850;