WHRN

Summary

WHRN (whirlin, HGNC:16361) is a protein-coding gene on chromosome 9q32, encoding Whirlin (Q9P202). Involved in hearing and vision as member of the USH2 complex.

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.

Source: NCBI Gene 25861 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Usher syndrome type 2D (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 958 total — 36 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 25
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_015404

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16361
Approved symbol	WHRN
Name	whirlin
Location	9q32
Locus type	gene with protein product
Status	Approved
Aliases	CIP98, USH2D, PDZD7B
Ensembl gene	ENSG00000095397
Ensembl biotype	protein_coding
OMIM	607928
Entrez	25861

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 13 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000265134, ENST00000362057, ENST00000374057, ENST00000480518, ENST00000673697, ENST00000673811, ENST00000674036, ENST00000674048, ENST00000699485, ENST00000699486, ENST00000866780, ENST00000866781, ENST00000929558, ENST00000929559, ENST00000929560, ENST00000929561

RefSeq mRNA: 4 — MANE Select: NM_015404 NM_001083885, NM_001173425, NM_001346890, NM_015404

CCDS: CCDS43870, CCDS6806

Canonical transcript exons

ENST00000362057 — 12 exons

Exon	Start	End
ENSE00000505590	114423314	114423523
ENSE00000722088	114403217	114403339
ENSE00000722092	114403896	114404077
ENSE00000722103	114407947	114408018
ENSE00000722107	114424334	114424546
ENSE00001141441	114424988	114425024
ENSE00001819045	114402080	114402936
ENSE00001904019	114504184	114505473
ENSE00003490158	114426211	114426413
ENSE00003546282	114466267	114466392
ENSE00003897698	114478553	114478771
ENSE00003976732	114406355	114406892

Expression profiles

Bgee: expression breadth ubiquitous, 226 present calls, max score 97.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.7114 / max 306.5357, expressed in 1487 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
102164	7.6808	1402
102163	3.5023	844
102162	0.2131	98
102161	0.1769	70
102160	0.1237	38
102165	0.0146	6

Top tissues by expression

286 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	97.42	gold quality
left adrenal gland	UBERON:0001234	97.40	gold quality
right adrenal gland	UBERON:0001233	97.38	gold quality
adrenal cortex	UBERON:0001235	97.35	gold quality
left adrenal gland cortex	UBERON:0035825	97.34	gold quality
adrenal gland	UBERON:0002369	96.06	gold quality
left testis	UBERON:0004533	95.53	gold quality
right testis	UBERON:0004534	95.45	gold quality
pituitary gland	UBERON:0000007	93.75	gold quality
right uterine tube	UBERON:0001302	93.51	gold quality
adenohypophysis	UBERON:0002196	93.41	gold quality
testis	UBERON:0000473	92.54	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	92.31	gold quality
body of uterus	UBERON:0009853	91.27	gold quality
spinal cord	UBERON:0002240	90.89	gold quality
adrenal tissue	UBERON:0018303	90.20	gold quality
left ovary	UBERON:0002119	88.84	gold quality
endocervix	UBERON:0000458	88.43	gold quality
spleen	UBERON:0002106	88.19	gold quality
right ovary	UBERON:0002118	87.75	gold quality
mucosa of stomach	UBERON:0001199	87.71	gold quality
oocyte	CL:0000023	87.66	gold quality
inferior vagus X ganglion	UBERON:0005363	86.94	gold quality
substantia nigra	UBERON:0002038	86.81	gold quality
midbrain	UBERON:0001891	86.75	gold quality
inferior olivary complex	UBERON:0002127	86.62	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	86.59	gold quality
hypothalamus	UBERON:0001898	86.18	gold quality
putamen	UBERON:0001874	85.76	gold quality
lateral globus pallidus	UBERON:0002476	85.38	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

35 targeting WHRN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-10393-5P	99.65	68.01	1368
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-6796-3P	98.68	65.49	689
HSA-MIR-619-5P	98.57	64.97	1988

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• This paper describes a PDZ domain protein and its role in synaptic transmission in the related rat gene. (PMID:12641734)
• Defects in whirlin, a PDZ domain molecule involved in stereocilia elongation, cause deafness in the whirler mouse and families with DFNB31. (PMID:12833159)
• This paper concludes that this protein plays a role in photoreceptor and hair cell synapse organization in the related rat gene. (PMID:16434480)
• analysis of a novel genetic subtype for Usher syndrome, USH2D, which is caused by mutations in whirlin (PMID:17171570)
• Overexpression of the signal peptide whirlin isoform 2 is related to disease progression in colorectal cancer patients. (PMID:19724906)
• DFNB31 is not a major cause of Usher syndrome. (PMID:20352026)
• A novel DFNB31 mutation associated with Usher type 2 syndrome showing variable degrees of auditory loss in a consanguineous Portuguese family. (PMID:21738389)
• Mutation found in USH2A, GPR98, or DFNB31 account for the vast majority of USH2 patients and their analysis provide a robust pathway for routine molecular diagnosis. (PMID:22147658)
• In Spain, USH2A and GPR98 are responsible for 95.8% and 5.2% of Usher syndrome 2 mutated cases, respectively. DFNB31 plays a minor role in the Spanish population. There was a group of patients in whom no mutation was found. (PMID:23441107)
• Data indicate that that CIB2 localizes to stereocilia and interacts with the USH proteins myosin VIIa and whirlin, suggesting CIB2 is a Ca2+-buffering protein essential for calcium homeostasis in the mechanosensory stereocilia of inner ear hair cells. (PMID:24022220)
• Protein-protein interaction assays and co-expression of complex partners reveal that pathogenic mutations in USH1G severely affect formation of the SANS/ush2a/whirlin complex. Translational read-through drug treatment, targeting the c.728C > A (p.S243X) nonsense mutation, restored SANS scaffold function. We conclude that USH1 and USH2 proteins function together in higher order protein complexes. (PMID:28137943)
• two novel mutations in the WHRN and TMC1 genes are responsible for founder effects of hereditary hemochromatosis, Wilson s disease, the long QT syndrome and autosomal recessive deafness in a Swedish pedigree (PMID:29270100)
• Usher syndrome and non-syndromic deafness: Functions of different whirlin isoforms in the cochlea, vestibular organs, and retina. (PMID:30831381)
• whirlin-espin interaction is important for the architecture of the USH2 complex and actin bundles cross-linked by espin. Our demonstration of whirlin N-terminal fragment interaction with espin, is significantly novel, providing insight into how these two proteins interact to form the USH2 complex. (PMID:31638198)
• Folding and Misfolding of a PDZ Tandem Repeat. (PMID:33539879)
• Phase separation-mediated condensation of Whirlin-Myo15-Eps8 stereocilia tip complex. (PMID:33626355)
• Novel pathogenic WHRN variant causing hearing loss in a moroccan family. (PMID:37924449)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	whrnb	ENSDARG00000068166
danio_rerio	whrna	ENSDARG00000075362
mus_musculus	Whrn	ENSMUSG00000039137
rattus_norvegicus	Whrn	ENSRNOG00000001700

Paralogs (2): USH1C (ENSG00000006611), PDZD7 (ENSG00000186862)

Protein

Protein identifiers

Whirlin — Q9P202 (reviewed: Q9P202)

Alternative names: Autosomal recessive deafness type 31 protein

All UniProt accessions (6): Q9P202, A0A669KBA5, A0A669KBJ1, A0A8V8TNT0, A0A8V8TQ31, B9EGE6

UniProt curated annotations — full annotation on UniProt →

Function. Involved in hearing and vision as member of the USH2 complex. Necessary for elongation and maintenance of inner and outer hair cell stereocilia in the organ of Corti in the inner ear. Involved in the maintenance of the hair bundle ankle region, which connects stereocilia in cochlear hair cells of the inner ear. In retina photoreceptors, required for the maintenance of periciliary membrane complex that seems to play a role in regulating intracellular protein transport.

Subunit / interactions. Forms homooligomers. Interacts (via C-terminal PDZ domain) with MYO15A; this interaction is necessary for localization of WHRN to stereocilia tips. Interacts (via C-terminal PDZ domain) with MPP1/p55. Interacts with LRRC4C/NGL1. Interacts with MYO7A. Interacts with RPGR. Interacts with EPS8. Interacts with CASK. Interacts with CIB2. Component of USH2 complex, composed of ADGRV1, PDZD7, USH2A and WHRN. Interacts (via PDZ domains) with PDZD7; the interaction is direct. Interacts (via N-terminal PDZ domain) with USH2A (via cytoplasmic region). Interacts with ADGRV1/MASS1 (via cytoplasmic region).

Subcellular location. Cytoplasm. Cell projection. Stereocilium. Growth cone. Photoreceptor inner segment. Synapse.

Disease relevance. 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. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be due to an intron retention.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9P202-1	1	yes
Q9P202-2	2
Q9P202-3	3
Q9P202-4	4

RefSeq proteins (4): NP_001077354, NP_001166896, NP_001333819, NP_056219* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR033028	Whirlin_HN-like_dom2	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR047056	Whirlin_HN-like_dom1	Domain
IPR051844	USH2_Complex_Protein	Family

Pfam: PF00595

UniProt features (59 total): strand 18, sequence variant 10, helix 6, compositionally biased region 5, splice variant 5, region of interest 5, domain 3, turn 3, sequence conflict 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6KZ1	X-RAY DIFFRACTION	1.69
7EP7	X-RAY DIFFRACTION	2.6
1UEZ	SOLUTION NMR
1UF1	SOLUTION NMR
1UFX	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P202-F1	59.39	0.09

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 685

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 218 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, NKX25_02, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, PEREZ_TP63_TARGETS, ZHAN_MULTIPLE_MYELOMA_MF_UP, GOBP_CEREBELLAR_PURKINJE_CELL_LAYER_FORMATION, GOBP_CEREBELLAR_CORTEX_MORPHOGENESIS, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_NEUROGENESIS, GOCC_MICROTUBULE_ORGANIZING_CENTER, EFC_Q6

GO Biological Process (12): retina homeostasis (GO:0001895), sensory perception of sound (GO:0007605), positive regulation of gene expression (GO:0010628), cerebellar Purkinje cell layer formation (GO:0021694), establishment of protein localization (GO:0045184), detection of mechanical stimulus involved in sensory perception of sound (GO:0050910), sensory perception of light stimulus (GO:0050953), establishment of localization in cell (GO:0051649), auditory receptor cell stereocilium organization (GO:0060088), inner ear receptor cell differentiation (GO:0060113), inner ear receptor cell stereocilium organization (GO:0060122), paranodal junction maintenance (GO:1990227)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (19): photoreceptor inner segment (GO:0001917), stereocilia ankle link (GO:0002141), stereocilia ankle link complex (GO:0002142), cytoplasm (GO:0005737), actin filament (GO:0005884), plasma membrane (GO:0005886), cilium (GO:0005929), growth cone (GO:0030426), photoreceptor connecting cilium (GO:0032391), stereocilium (GO:0032420), stereocilium tip (GO:0032426), ciliary basal body (GO:0036064), synapse (GO:0045202), periciliary membrane compartment (GO:1990075), USH2 complex (GO:1990696), stereocilium bundle (GO:0032421), cell projection (GO:0042995), neuron projection (GO:0043005), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
establishment of localization	2
protein-containing complex	2
plasma membrane bounded cell projection	2
stereocilium	2
tissue homeostasis	1
sensory perception of mechanical stimulus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cerebellar Purkinje cell layer morphogenesis	1
cerebellar cortex formation	1
anatomical structure formation involved in morphogenesis	1
sensory perception of sound	1
nervous system process	1
detection of mechanical stimulus involved in sensory perception	1
sensory perception	1
cellular localization	1
auditory receptor cell morphogenesis	1
inner ear receptor cell stereocilium organization	1
mechanoreceptor differentiation	1
inner ear development	1
neuron projection development	1
inner ear receptor cell development	1
cell-cell junction maintenance	1
protein binding	1
binding	1
stereocilia coupling link	1
stereocilia ankle link	1
intracellular anatomical structure	1
actin cytoskeleton	1
polymeric cytoskeletal fiber	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
site of polarized growth	1
distal axon	1
ciliary transition zone	1
photoreceptor cell cilium	1

Protein interactions and networks

STRING

1240 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
WHRN	USH2A	O75445	999
WHRN	ADGRV1	Q8WXG9	999
WHRN	MYO15A	Q9UKN7	998
WHRN	USH1G	Q495M9	992
WHRN	MYO7A	P78427	965
WHRN	CDH23	Q9H251	943
WHRN	EPS8	Q12929	941
WHRN	LRRC4C	Q9HCJ2	898
WHRN	E9PNW1	E9PNW1	896
WHRN	PCDH15	Q96QU1	892
WHRN	CLRN1	P58418	890
WHRN	CIB2	O75838	861
WHRN	PDZD7	Q9H5P4	817
WHRN	TMC1	Q8TDI8	808
WHRN	ESPN	B1AK53	788

IntAct

1232 interactions, top by confidence:

A	B	Type	Score
LRP4	WHRN	psi-mi:“MI:0915”(physical association)	0.590
WHRN	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
GOLGA2	WHRN	psi-mi:“MI:0915”(physical association)	0.560
DDIT4L	WHRN	psi-mi:“MI:0915”(physical association)	0.560
GPSM2	WHRN	psi-mi:“MI:0915”(physical association)	0.560
WHRN	COL17A1	psi-mi:“MI:0915”(physical association)	0.560
PXN	WHRN	psi-mi:“MI:0915”(physical association)	0.560
KEAP1	WHRN	psi-mi:“MI:0915”(physical association)	0.560
TPRN	WHRN	psi-mi:“MI:0915”(physical association)	0.560
	WHRN	psi-mi:“MI:0915”(physical association)	0.560
BEND7	WHRN	psi-mi:“MI:0915”(physical association)	0.560
EFHC1	WHRN	psi-mi:“MI:0915”(physical association)	0.560
SPC24	WHRN	psi-mi:“MI:0915”(physical association)	0.560
BMI1	WHRN	psi-mi:“MI:0915”(physical association)	0.560
MCC	WHRN	psi-mi:“MI:0407”(direct interaction)	0.550
E6	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
WHRN	PTEN	psi-mi:“MI:0407”(direct interaction)	0.440
LRRC4	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM22	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
YAP1	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
WHRN	WWTR1	psi-mi:“MI:0407”(direct interaction)	0.440
LRRC4B	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
WHRN	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.440
WHRN	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
WHRN	SEMA4F	psi-mi:“MI:0407”(direct interaction)	0.440
WHRN	MAP4	psi-mi:“MI:0407”(direct interaction)	0.440
ADRA1D	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A5	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (27): TBK1 (Affinity Capture-MS), TBKBP1 (Affinity Capture-MS), MCC (Affinity Capture-MS), PXN (Affinity Capture-MS), WDTC1 (Affinity Capture-MS), ANKRD28 (Affinity Capture-MS), HSP90AB2P (Affinity Capture-MS), XPNPEP3 (Affinity Capture-MS), VIM (Affinity Capture-MS), DFNB31 (Protein-peptide), DFNB31 (Two-hybrid), DFNB31 (Two-hybrid), DFNB31 (Two-hybrid), EFHC1 (Two-hybrid), GPSM2 (Two-hybrid)

ESM2 similar proteins: A3KMV1, B9EHT4, D3YWQ0, D5SHR0, F1MAB7, F5HB62, O42406, O75426, O75592, O75912, O95343, P03177, P0C5J9, P42859, P51111, P59114, P59438, Q04725, Q08274, Q0VD00, Q1HVD1, Q2TAL5, Q3KSQ2, Q3V0G7, Q4G017, Q4R327, Q4VC12, Q5R686, Q5U464, Q5VVW2, Q6NRL1, Q6P7W2, Q7TPH6, Q80TM9, Q80VW5, Q810W9, Q8BFX3, Q8CH72, Q8CI12, Q8K0E1

Diamond homologs: A0A0G2K2P5, A0A8P0N4K0, C5IAW9, F1LW30, O08721, O08722, O08747, O62683, O95049, O95185, O97758, P39447, P57105, Q07157, Q0P5E6, Q13424, Q28626, Q32LE7, Q3T0C9, Q5EBL8, Q5ZIK2, Q61234, Q6NXB2, Q6QA76, Q6R653, Q6UXZ4, Q6ZN44, Q761X5, Q7KRY7, Q7T2Z5, Q80VW5, Q86UL8, Q8IV45, Q8IZJ1, Q8JGT4, Q8K1S2, Q8K1S3, Q8K1S4, Q95168, Q9CZG9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
WHRN	“form complex”	“USH2 complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 150 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
phospholipase C-activating G protein-coupled receptor signaling pathway	8	7.6×	6e-03
cell adhesion	14	3.8×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

958 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	15
Uncertain significance	443
Likely benign	322
Benign	50

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072887	NM_015404.4(WHRN):c.1958_1959dup (p.Val654fs)	Pathogenic
1074701	NM_015404.4(WHRN):c.1573_1574del (p.Thr525fs)	Pathogenic
1367138	NM_015404.4(WHRN):c.1312del (p.Glu438fs)	Pathogenic
1377058	NM_015404.4(WHRN):c.157_166del (p.Ala53fs)	Pathogenic
1397367	NM_015404.4(WHRN):c.501del (p.Ile166_Tyr167insTer)	Pathogenic
1442336	NM_015404.4(WHRN):c.74dup (p.Gly26fs)	Pathogenic
1446808	NM_015404.4(WHRN):c.209del (p.Asn70fs)	Pathogenic
1451408	NM_015404.4(WHRN):c.1822C>T (p.Gln608Ter)	Pathogenic
1457607	NM_015404.4(WHRN):c.929_948dup (p.Gly317fs)	Pathogenic
2033148	NM_015404.4(WHRN):c.1265dup (p.Arg423fs)	Pathogenic
208207	NM_015404.4(WHRN):c.2423del (p.Gly808fs)	Pathogenic
2101433	NM_015404.4(WHRN):c.1563del (p.Tyr522fs)	Pathogenic
2122115	NM_015404.4(WHRN):c.366C>A (p.Tyr122Ter)	Pathogenic
2134162	NM_015404.4(WHRN):c.154G>T (p.Glu52Ter)	Pathogenic
2500690	NM_015404.4(WHRN):c.35C>A (p.Ser12Ter)	Pathogenic
2503092	NM_015404.4(WHRN):c.1817del (p.Asp606fs)	Pathogenic
2689	NM_015404.4(WHRN):c.2332C>T (p.Arg778Ter)	Pathogenic
2690	NM_015404.4(WHRN):c.307C>T (p.Gln103Ter)	Pathogenic
2691	NM_015404.4(WHRN):c.837+1G>A	Pathogenic
2745850	NM_015404.4(WHRN):c.327C>A (p.Tyr109Ter)	Pathogenic
2791604	NM_015404.4(WHRN):c.1519C>T (p.Gln507Ter)	Pathogenic
2971028	NM_015404.4(WHRN):c.73_88del (p.Gly25fs)	Pathogenic
2981511	NM_015404.4(WHRN):c.2118_2121del (p.Ser707fs)	Pathogenic
31704	NM_015404.4(WHRN):c.737del (p.Pro246fs)	Pathogenic
31705	NM_015404.4(WHRN):c.680dup (p.Tyr228fs)	Pathogenic
3601042	NM_015404.4(WHRN):c.2430_2445del (p.Glu811fs)	Pathogenic
3616226	NM_015404.4(WHRN):c.23_26dup (p.Ser11fs)	Pathogenic
3629826	NM_015404.4(WHRN):c.1584dup (p.Thr529fs)	Pathogenic
45645	NM_015404.4(WHRN):c.1267C>T (p.Arg423Ter)	Pathogenic
45679	NM_015404.4(WHRN):c.643del (p.Val215fs)	Pathogenic

SpliceAI

2902 predictions. Top by Δscore:

Variant	Effect	Δscore
9:114402935:CT:C	acceptor_gain	1.0000
9:114403212:CATA:C	donor_loss	1.0000
9:114403213:ATAC:A	donor_loss	1.0000
9:114403214:TACC:T	donor_loss	1.0000
9:114403215:A:AC	donor_gain	1.0000
9:114403215:ACC:A	donor_loss	1.0000
9:114403216:C:CC	donor_gain	1.0000
9:114403335:CCAGG:C	acceptor_gain	1.0000
9:114403336:CAGG:C	acceptor_gain	1.0000
9:114403336:CAGGC:C	acceptor_gain	1.0000
9:114403337:AGG:A	acceptor_gain	1.0000
9:114403338:GG:G	acceptor_gain	1.0000
9:114403339:GCTG:G	acceptor_loss	1.0000
9:114403340:C:CC	acceptor_gain	1.0000
9:114403342:G:C	acceptor_gain	1.0000
9:114403890:GCTCA:G	donor_loss	1.0000
9:114403891:CTCA:C	donor_loss	1.0000
9:114403892:TCA:T	donor_loss	1.0000
9:114403893:CACCG:C	donor_loss	1.0000
9:114403894:A:AC	donor_gain	1.0000
9:114403894:ACCG:A	donor_loss	1.0000
9:114403895:C:CC	donor_gain	1.0000
9:114404075:CTG:C	acceptor_gain	1.0000
9:114404076:TG:T	acceptor_gain	1.0000
9:114408015:TGTT:T	acceptor_gain	1.0000
9:114408019:C:CC	acceptor_gain	1.0000
9:114424409:AT:A	donor_gain	1.0000
9:114424543:CTGG:C	acceptor_gain	1.0000
9:114424547:C:CC	acceptor_gain	1.0000
9:114424547:CT:C	acceptor_loss	1.0000

AlphaMissense

5789 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:114504239:A:G	I188T	1.000
9:114504341:A:G	F154S	1.000
9:114504485:A:G	F106S	1.000
9:114504521:A:T	L94H	1.000
9:114504569:A:G	L78P	1.000
9:114504581:A:G	L74P	1.000
9:114504609:A:C	Y65D	1.000
9:114504617:A:G	L62P	1.000
9:114504629:A:G	F58S	1.000
9:114402785:A:G	F898S	0.999
9:114403269:A:T	I830N	0.999
9:114478684:A:G	W236R	0.999
9:114478684:A:T	W236R	0.999
9:114478743:A:G	L216P	0.999
9:114504192:C:G	A204P	0.999
9:114504239:A:C	I188S	0.999
9:114504239:A:T	I188N	0.999
9:114504299:A:T	V168E	0.999
9:114504329:C:T	G158E	0.999
9:114504335:A:T	I156N	0.999
9:114504484:G:C	F106L	0.999
9:114504484:G:T	F106L	0.999
9:114504485:A:C	F106C	0.999
9:114504486:A:G	F106L	0.999
9:114504497:T:A	D102V	0.999
9:114504497:T:C	D102G	0.999
9:114504509:A:T	I98N	0.999
9:114504512:A:T	V97D	0.999
9:114504521:A:G	L94P	0.999
9:114504533:A:G	L90P	0.999

dbSNP variants (sampled 300 via entrez): RS1000094479 (9:114446879 T>C), RS1000099113 (9:114500024 T>C), RS1000113540 (9:114462374 T>C), RS1000180566 (9:114439687 A>T), RS1000224460 (9:114438258 A>G), RS1000247295 (9:114482652 C>G), RS1000255095 (9:114413167 T>C), RS1000259253 (9:114444175 G>T), RS1000311237 (9:114405675 C>A,T), RS1000338538 (9:114456600 G>A), RS1000375897 (9:114457632 T>C), RS1000383385 (9:114407489 A>G), RS1000423004 (9:114411176 A>T), RS1000483442 (9:114488592 C>A), RS1000489787 (9:114451756 T>A,C)

Disease associations

OMIM: gene MIM:607928 | disease phenotypes: MIM:607084, MIM:611383, MIM:276900, MIM:500004, MIM:220290, MIM:607197, MIM:300600

GenCC curated gene-disease

Disease	Classification	Inheritance
Usher syndrome type 2D	Definitive	Unknown
autosomal recessive nonsyndromic hearing loss 31	Strong	Autosomal recessive
nonsyndromic genetic hearing loss	Moderate	Autosomal recessive
Usher syndrome type 2	Supportive	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Moderate	AR
Usher syndrome type 2D	Definitive	AR

Mondo (11): autosomal recessive nonsyndromic hearing loss 31 (MONDO:0011767), Usher syndrome type 2D (MONDO:0012662), hearing loss disorder (MONDO:0005365), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), Usher syndrome (MONDO:0019501), retinitis pigmentosa-deafness syndrome (MONDO:0010775), hearing loss, autosomal recessive (MONDO:0019588), Aland island eye disease (MONDO:0010371), nonsyndromic genetic hearing loss (MONDO:0019497), Usher syndrome type 2 (MONDO:0016484)

Orphanet (7): Usher syndrome type 2 (Orphanet:231178), Usher syndrome (Orphanet:886), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Rare genetic deafness (Orphanet:96210), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Åland Islands eye disease (Orphanet:178333)

HPO phenotypes

25 total (26 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000359	Abnormality of the inner ear
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000545	Myopia
HP:0000551	Color vision defect
HP:0000572	Visual loss
HP:0000575	Scotoma
HP:0000662	Nyctalopia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001133	Constriction of peripheral visual field
HP:0001751	Abnormal vestibular function
HP:0002141	Gait imbalance
HP:0002360	Sleep disturbance
HP:0003577	Congenital onset
HP:0007663	Reduced visual acuity
HP:0007730	Iris hypopigmentation
HP:0007994	Peripheral visual field loss
HP:0008555	Absent vestibular function
HP:0012378	Fatigue
HP:0032036	Reduced contrast sensitivity
HP:0000556	Retinal dystrophy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001762_98	Obesity-related traits	2.000000e-08
GCST003090_3	Depressive and manic episodes in bipolar disorder	5.000000e-07
GCST003091_1	Depressive episodes in bipolar disorder	9.000000e-09
GCST004485_10	Survival in pancreatic cancer	7.000000e-06
GCST011998_6	Glucocorticoid receptor gene expression in B-cell precursor acute lymphoblastic leukaemia	6.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007704	depressive episode measurement
EFO:0007705	manic episode measurement
EFO:0000638	overall survival

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D058499	Retinal Dystrophies	C11.768.585.658
D052245	Usher Syndromes	C09.218.458.341.186.500.500; C09.218.458.341.887.886; C10.597.751.418.341.186.500.500; C10.597.751.418.341.887.886; C10.597.751.941.162.625.500; C11.768.585.658.500.813; C11.966.075.375.500; C16.131.077.299.500; C16.320.290.684.500; C23.888.592.763.393.341.887.886
C562664	Aland Island Eye Disease (supp.)
C564609	Deafness, Autosomal Recessive (supp.)
C564629	Deafness, Autosomal Recessive 31 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

35 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Valproic Acid	affects expression, increases methylation	2
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	increases expression	1
di-n-butylphosphoric acid	affects expression	1
pentabromodiphenyl ether	increases expression	1
CGP 52608	increases reaction, affects binding	1
clothianidin	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Cisplatin	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Lead	affects expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Thiram	increases expression	1
Urethane	increases expression	1

Clinical trials (associated diseases)

307 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT05158296	PHASE2/PHASE3	TERMINATED	Study to Evaluate the Efficacy Safety and Tolerability of Ultevursen in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene (Sirius)
NCT05176717	PHASE2/PHASE3	TERMINATED	Study to Evaluate the Efficacy Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene With Early to Moderate Vision Loss (Celeste)
NCT03780257	PHASE1/PHASE2	COMPLETED	Study to Evaluate Safety and Tolerability of QR-421a in Subjects With RP Due to Mutations in Exon 13 of the USH2A Gene
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People