WHRN

protein-coding

whirlin, the group of PDZ domain containing|USH2 complex

Gene summary

This gene is thought to function in the organization and stabilization of sterocilia elongation and actin cystoskeletal assembly, based on studies of the related mouse gene. Mutations in this gene have been associated with autosomal recessive non-syndromic deafness and Usher Syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

Previous symbols:

DFNB31

MANE transcript

NM_015404.4

Inheritance

ClinVar variants

P:63U:435B:314

Top phenotype

Usher syndrome, type 2D; Deafness, autosomal recessive 31

gnomAD constraint

pLI —, LoF o/e 0.41

Max pathogenic AF

—

Genomic locus

chr9:114,402,078-114,505,473

External References & Databases

Ensembl (ENSG00000095397)

Transcript & Mutation Effects

hg38 • Region Span ~103.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 31STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011767

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

WHRN was first reported in relation to autosomal recessive nonsyndromic genetic hearing loss in 2002 (Mustapha et al., PMID: 11973626). Three variants (nonsense and frameshift) that have been reported in 3 probands in 3 publications (PMIDs: 12833159, 29270100, 34194829) are included in this curation. Variants in this gene segregated with disease in 12 additional family members from 3 separate families. Many additional cases have been reported in the literature claiming autosomal recessive nonsyndromic hearing loss with WHRN variants; however, these variants were not scored due to a lack of convincing phenotyping to rule out late onset retinitis pigmentosa in the probands (i.e. patient is below age of RP onset for Usher type 2, age is not reported, eye examination is not reported) (PMIDs: 23767834, 24194196, 26561413, 26969326, 27344577, 27610647, 28600779, 30303587). The mechanism of pathogenicity is known to be loss-of-function. This gene-disease association is also supported by expression in the cochlea, and two separate mouse models phenocopying nonsyndromic genetic hearing loss in humans (PMID: 27117407). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Hearing Loss GCEP on January 2, 2019. It was reevaluated on January 17, 2024. As a result of this reevaluation, the classification did not change.

autosomal recessive nonsyndromic hearing loss 31MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011767

Submitter: Ambry Genetics

Usher syndrome type 2DMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0012662

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 31STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011767

Submitter: PanelApp Australia

Usher syndrome type 2DDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012662

Submitter: G2P

Usher syndrome type 2DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012662

Submitter: Labcorp Genetics (formerly Invitae)

Usher syndrome type 2DDEFINITIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0012662

Submitter: ClinGen

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

Usher syndrome type 2DSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012662

Submitter: PanelApp Australia

Usher syndrome type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016484

Submitter: Orphanet

Clinical Genomic Database (CGD)

Usher syndrome, type 2D; Deafness, autosomal recessive 31AR

Manifestation: Audiologic/Otolaryngologic; Ophthalmologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 12833159; 17171570

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WHRN variants in ClinVar

17 Conditions Cataloged

not providedTotal: 841

not specifiedTotal: 186

Autosomal recessive nonsyndromic hearing loss 31Total: 110

Usher syndrome type 2DTotal: 109

WHRN-related disorderTotal: 64

Inborn genetic diseasesTotal: 14

Retinal dystrophyTotal: 10

Usher syndromeTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015404.4. 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			8 clinvar	271 clinvar	2 clinvar	281
missense		1 clinvar	422 clinvar	35 clinvar	6 clinvar	464
nonsense	13 clinvar	6 clinvar	1 clinvar			20
start loss			2 clinvar			2
frameshift	20 clinvar	10 clinvar				30
splice donor/acceptor (+/-2bp)	1 clinvar	12 clinvar	2 clinvar			15
Total	34	29	435	306	8	812

Highest pathogenic variant AF is 0.000039658982

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015404.4	RefSeq	NP_056219.3	12	MANE Select
ENST00000362057.4	Ensembl	ENSP00000354623.3	12	MANE Select
NM_001083885.3	RefSeq	NP_001077354.2	9	Standard
NM_001173425.2	RefSeq	NP_001166896.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

retina homeostasis
sensory perception of sound
positive regulation of gene expression
cerebellar Purkinje cell layer formation
establishment of protein localization

Molecular Function

protein binding
protein homodimerization activity
protein heterodimerization activity

Cellular Component

photoreceptor inner segment
stereocilia ankle link
stereocilia ankle link complex
cytoplasm
actin filament

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000362057
Coding exons: 12
Length: 103371
Individuals with no LoFs: 125695
Homozygous LoFs: 0
Heterozygous LoFs: 53
Defined: 125748
p: 0.000211

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.325	580	558	1.04	0.0000378	5703
Missense (PolyPhen)		192	200.8	0.95617		2122
Synonymous	-0.445	264	255	1.04	0.0000184	2053
Loss of Function	2.94	12	29.1	0.412	0.00000146	330

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00018	0.00018	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00030	0.00029	rare
South Asian	0.00036	0.00036	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Necessary for elongation and maintenance of inner and outer hair cell stereocilia in the organ of Corti in the inner ear. {ECO:0000250}.;
Disease: DISEASE: Deafness, autosomal recessive, 31 (DFNB31) [MIM:607084]: 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:11973626, ECO:0000269|PubMed:12833159, ECO:0000269|PubMed:15841483}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Usher syndrome 2D (USH2D) [MIM:611383]: USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa and sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH2 is characterized by congenital mild hearing impairment with normal vestibular responses. {ECO:0000269|PubMed:17171570}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.165

Intolerance Scores

RVIS EVS: 0.64
RVIS percentile EVS: 83.65

Essentials

Essential (gene trap): N