WBP2

protein-coding

WW domain binding protein 2, the group of GRAM domain containing

Gene summary

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]

MANE transcript

NM_012478.4

Inheritance

ClinVar variants

P:1U:86B:29

Top phenotype

Deafness, autosomal recessive 107

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr17:75,845,699-75,856,507

External References & Databases

Ensembl (ENSG00000132471)

Transcript & Mutation Effects

hg38 • Region Span ~10.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: ClinGen

The WBP2 gene was reported in association with autosomal recessive nonsyndromic hearing loss (ARNSHL) in 2016 (Buniello et al.) based on observations of three missense variants in three probands with NSHL. However, insufficient evidence for pathogenicity of any of the three variants was presented and so none of the human evidence was scored in the ClinGen framework. The gene was shown to be expressed in mouse inner ear tissue and a mouse model with a homozygous knockout of the WBP2 gene showed progressive, later-onset HL compared to their wildtype littermates (Buniello et al. 2016). In summary, although the mouse model suggests that the WBP2 gene is a strong candidate for human hearing loss, none of the human cases presented to date have evidence to implicate WBP2 and therefore the final conclusion is limited in the ClinGen gene-disease validity framework. This classification was approved by the ClinGen Hearing Loss Working Group on 11/20/2018.

hearing loss, autosomal recessive 107LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033199

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessive 107MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0033199

Submitter: PanelApp Australia

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 107AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 26881968

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WBP2 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 104

not specifiedTotal: 58

WBP2-related disorderTotal: 12

Hearing loss, autosomal recessive 107Total: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_012478.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	24 clinvar	2 clinvar	27
missense		1 clinvar	83 clinvar	3 clinvar		87
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	0	1	86	27	2	116

Highest pathogenic variant AF is 6.8485554e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_012478.4	RefSeq	NP_036610.2	8	MANE Select
ENST00000254806.8	Ensembl	ENSP00000254806.3	8	MANE Select
NM_001330499.2	RefSeq	NP_001317428.1	7	Standard
NM_001348170.1	RefSeq	NP_001335099.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

EGFR1

Biological Process

response to progesterone
positive regulation of intracellular estrogen receptor signaling pathway
response to estrogen
establishment of protein localization
positive regulation of gene expression, epigenetic

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
transcription coactivator activity
protein binding
estrogen receptor binding
chromatin DNA binding

Cellular Component

nuclear chromatin
nucleus
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000591399
Coding exons: 8
Length: 10809
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125747
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.296	151	162	0.934	0.00000909	1687
Missense (PolyPhen)		42	46.847	0.89653		544
Synonymous	-0.214	67	64.8	1.03	0.00000438	495
Loss of Function	2.59	3	13.1	0.229	5.53e-7	166

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0	0.0	absent
South Asian	0.000034	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as transcriptional coactivator of estrogen and progesterone receptors (ESR1 and PGR) upon hormone activation (PubMed:16772533). In presence of estrogen, binds to ESR1- responsive promoters (PubMed:16772533). Required for YAP1 coactivation function on PGR activity (PubMed:16772533). Synergizes with WBP2 in enhancing PGR activity (PubMed:16772533). Modulates expression of post-synaptic scaffolding proteins via regulation of ESR1, ESR2 and PGR (By similarity). {ECO:0000250|UniProtKB:P97765, ECO:0000269|PubMed:16772533}.;
Disease: DISEASE: Deafness, autosomal recessive, 107 (DFNB107) [MIM:617639]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:26881968}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.130

Intolerance Scores

LoFtool: 0.350
RVIS EVS: -0.03
RVIS percentile EVS: 51.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.988

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium