17-75846755-C-G

Variant names:

• chr17-75846755-C-G
• rs372580353
• NM_012478.4:c.765G>C

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_012478.4(WBP2):​c.765G>C​(p.Pro255Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000723 in 1,382,300 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. Synonymous variant affecting the same amino acid position (i.e. P255P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: WBP2 NM_012478.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.848
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.116142064).
• BP7: Synonymous conserved (PhyloP=-0.848 with no splicing effect.

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.765G>C	p.Pro255Pro	synonymous	Exon 8 of 8	NP_036610.2
	WBP2	NM_001348170.1		c.765G>C	p.Pro255Pro	synonymous	Exon 9 of 9	NP_001335099.1	Q969T9-1
	WBP2	NM_001330499.2		c.630G>C	p.Pro210Pro	synonymous	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.765G>C	p.Pro255Pro	synonymous	Exon 8 of 8	ENSP00000254806.3	Q969T9-1
	WBP2	ENST00000626827.2	TSL:5	c.688G>C	p.Gly230Arg	missense	Exon 7 of 7	ENSP00000486675.1	K7ENL2
	WBP2	ENST00000591399.5	TSL:5	c.765G>C	p.Pro255Pro	synonymous	Exon 9 of 9	ENSP00000467579.1	Q969T9-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.23e-7 AC: 1 AN: 1382300 Hom.: 0 Cov.: 31 AF XY: 0.00000147 AC XY: 1 AN XY: 679612

African (AFR) AF: 0.00 AC: 0 AN: 31306

American (AMR) AF: 0.00 AC: 0 AN: 33706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22146

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37378

South Asian (SAS) AF: 0.00 AC: 0 AN: 74246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5490

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1071578

Other (OTH) AF: 0.00 AC: 0 AN: 57152

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	2.4
DANN	Benign	0.82
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.12	T
PhyloP100		-0.85
Sift4G	Uncertain	0.0070	D
Vest4		0.20
MVP		0.092
ClinPred		0.12	T
GERP RS		-7.7

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: rs372580353; hg19: chr17-73842836;