COCH

Summary

COCH (cochlin, HGNC:2180) is a protein-coding gene on chromosome 14q12, encoding Cochlin (O43405). Plays a role in the control of cell shape and motility in the trabecular meshwork.

The protein encoded by this gene is highly conserved in human, mouse, and chicken, showing 94% and 79% amino acid identity of human to mouse and chicken sequences, respectively. Hybridization to this gene was detected in spindle-shaped cells located along nerve fibers between the auditory ganglion and sensory epithelium. These cells accompany neurites at the habenula perforata, the opening through which neurites extend to innervate hair cells. This and the pattern of expression of this gene in chicken inner ear paralleled the histologic findings of acidophilic deposits, consistent with mucopolysaccharide ground substance, in temporal bones from DFNA9 (autosomal dominant nonsyndromic sensorineural deafness 9) patients. Mutations that cause DFNA9 have been reported in this gene. Alternative splicing results in multiple transcript variants encoding the same protein. Additional splice variants encoding distinct isoforms have been described but their biological validities have not been demonstrated.

Source: NCBI Gene 1690 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 326 total — 16 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 12
• MANE Select transcript: NM_004086

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2180
Approved symbol	COCH
Name	cochlin
Location	14q12
Locus type	gene with protein product
Status	Approved
Aliases	COCH-5B2
Ensembl gene	ENSG00000100473
Ensembl biotype	protein_coding
OMIM	603196
Entrez	1690

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 17 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000216361, ENST00000396618, ENST00000460581, ENST00000468826, ENST00000475087, ENST00000553772, ENST00000553833, ENST00000555117, ENST00000555881, ENST00000556908, ENST00000557065, ENST00000643575, ENST00000643697, ENST00000644874, ENST00000914778, ENST00000914779, ENST00000914780, ENST00000914781, ENST00000914782, ENST00000964788, ENST00000964789

RefSeq mRNA: 3 — MANE Select: NM_004086 NM_001135058, NM_001347720, NM_004086

CCDS: CCDS86382, CCDS9640

Canonical transcript exons

ENST00000396618 — 12 exons

Exon	Start	End
ENSE00000654637	30875056	30875103
ENSE00000654646	30885796	30886312
ENSE00001846907	30874559	30874591
ENSE00001953870	30889616	30890618
ENSE00002532891	30874916	30874972
ENSE00003618886	30877572	30877728
ENSE00003623480	30879423	30879485
ENSE00003654841	30884553	30884656
ENSE00003661274	30880452	30880496
ENSE00003688126	30878811	30878944
ENSE00003784790	30885394	30885620
ENSE00003785006	30880587	30880734

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 98.82.

FANTOM5 (CAGE): breadth broad, TPM avg 12.7048 / max 417.9840, expressed in 871 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
139098	9.0265	776
139096	2.0373	507
139097	1.3792	436
139099	0.2618	83

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	98.82	gold quality
saphenous vein	UBERON:0007318	98.80	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.65	gold quality
vena cava	UBERON:0004087	98.59	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.50	gold quality
pericardium	UBERON:0002407	98.47	gold quality
cauda epididymis	UBERON:0004360	98.34	gold quality
biceps brachii	UBERON:0001507	98.33	gold quality
body of tongue	UBERON:0011876	98.16	gold quality
superior surface of tongue	UBERON:0007371	98.03	gold quality
heart right ventricle	UBERON:0002080	97.87	gold quality
caput epididymis	UBERON:0004358	97.33	gold quality
pons	UBERON:0000988	97.25	gold quality
trigeminal ganglion	UBERON:0001675	97.25	gold quality
corpus epididymis	UBERON:0004359	97.23	gold quality
mucosa of paranasal sinus	UBERON:0005030	97.20	gold quality
tendon of biceps brachii	UBERON:0008188	96.99	gold quality
pharyngeal mucosa	UBERON:0000355	96.42	gold quality
medial globus pallidus	UBERON:0002477	96.04	gold quality
mammary duct	UBERON:0001765	95.96	gold quality
tongue	UBERON:0001723	95.81	gold quality
superior vestibular nucleus	UBERON:0007227	95.59	gold quality
epithelium of nasopharynx	UBERON:0001951	95.53	gold quality
globus pallidus	UBERON:0001875	95.21	gold quality
oocyte	CL:0000023	95.16	gold quality
secondary oocyte	CL:0000655	95.07	gold quality
superficial temporal artery	UBERON:0001614	95.03	gold quality
nucleus accumbens	UBERON:0001882	94.99	gold quality
mammalian vulva	UBERON:0000997	94.65	gold quality
trabecular bone tissue	UBERON:0002483	94.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting COCH, 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-3163	100.00	77.23	8605
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-1276	99.36	68.18	1642

Literature-anchored findings (GeneRIF, showing 40)

• Areas that express COCH mRNA as determined by in situ hybridization, and to the regions of the inner ear which show histological abnormalities in autosomal dominant sensorineural deafness and vestibular disorder, DFNA9. (PMID:11709536)
• findings suggest that COCH mutations are unlikely to cause abnormalities in secretion and suggest that extracellular events might cause autosomal dominant sensorineural deafness (DFNA9) pathology (PMID:12928864)
• A multigeneration Belgian family with late-onset progressive sensorineural hearing loss–Linkage to DFNA9 was confirmed and mutation analysis revealed a P51S mutation in the COCH gene. (PMID:14501450)
• Cochlin, a protein associated with deafness disorder DFNA9, is present in glaucomatous but absent in normal trabecular meshwork (PMID:15579465)
• A new COCH mutation is identified which causes autosomal dominant hearing impairment. (PMID:16835921)
• Cochlin-specific interferon-gamma-producing T cells are implicated in the etiopathogenesis of autoimmune sensorineural hearing loss. (PMID:16951386)
• Haplotype analysis placed the late onset autosomal dominant hereditary non-syndromic hearing loss locus within a 7.6 cM genetic interval defined by marker D14S1021 and D14S70, overlapping with the DFNA9 locus (PMID:17138532)
• the phenotype associated with the novel COCH (G87W) mutation is largely similar to that associated with the P51S and G88E mutation carriers (PMID:17264471)
• Data analysis demonstrated a significant association between vertical corneal striae and the Pro51Ser and Gly88Glu mutations in the COCH gene in DFNA9 families 1, 2, and 3 with cochleovestibular dysfunction. (PMID:17368553)
• This is a report of the audiological and vestibular characteristics of a Dutch DFNA9 family with a novel mutation, I109T, in the LCCL domain of COCH (PMID:17561763)
• A prominent but previously unreported ribbon-like pattern of cochlin in the basilar membrane was demonstrated, suggesting an important role for cochlin in the structure of the basilar membrane. (PMID:17926100)
• All affected family members with a COCH mutation in the vWFA2 domain shared sensorineural hearing loss with full penetrance starting between the second and fifth decade of life. (PMID:17944208)
• novel mutations in the vWFA2 domain of the COCH gene were identified in Chinese families with autosomal dominant sensorineural non-syndromic hearing loss (HL) 9 (PMID:18312449)
• The second von Willebrand type A domain of cochlin has affinity for type II collagen, as well as type I and type IV collagens whereas the LCCL-domain of cochlin has no affinity for these proteins. (PMID:19013156)
• These results support the finding that the observed increased cochlin expression in glaucomatous TM is due to relative elevated abundance of transcription factors. (PMID:19098315)
• causative mutation in the COCH gene in American families associated with superior semicircular canal dehiscence.(280-5) (PMID:19161137)
• By RT-PCR, we found that full-length cochlin was expressed in all organs examined, with a splice variant in the heart. By Western blot, we detected short isoforms (11-17 kDa) in the perilymph. (PMID:19657184)
• Cochlin expression was effective in decreasing outflow facility and increasing pressure in cultured anterior segment, suggesting possible involvement of cochlin in IOP elevation in vivo. (PMID:19933177)
• present in the perilymph, not in cerebrospinal fluid (PMID:20105107)
• study suggests a possible molecular mechanism underlying DFNA9 hearing loss and provides an in vitro model that may be used to explore protein-misfolding diseases in genera (PMID:20228067)
• The causative gene of autosomal dominant non-syndromic hearing loss in the Korean family and a recurrent mutation in the COCH gene, were identified. (PMID:20447147)
• The onset of the hearing loss, in the 2nd or 3rd decade of life, is earlier than in most DFNA9 families. The progression of hearing loss and vestibular dysfunction in the American family is typical of other DFNA9 families with mutations in this domain. (PMID:21046548)
• The phenotype associated with the I109N COCH mutation is largely similar to that associated with the I109T, P51S, G87W, and G88E mutation carriers. However, subtle differences seem to exist in terms of age of onset and rate of progression. (PMID:21774451)
• Cochlin interacts with TREK-1 and annexin A2. (PMID:21886777)
• The data cannot confirm the association described previously between superior semicircular canal dehiscence and the presence of mutations in COCH gene. (PMID:22139968)
• the instability of mutant cochlin is the major driving force for cochlin aggregation in the inner ear in DFNA9 patients carrying the COCH p.F527C mutation (PMID:22610276)
• Identification of a novel missense mutation in COCH in a Chinese family with autosomal dominant non-syndromic progressive sensorineural hearing loss. (PMID:22931125)
• COCH and SLC26A5 mRNA are expressed in specific structures and cells of the inner ear in archival human temporal bone (PMID:23660400)
• Chinese DFNA9 family associated with novel COCH mutation with genotype-phenotype correlation. (PMID:23993205)
• This study suggests lack of association of both COCH and TNFA with primary open-angle glaucoma pathogenesis. (PMID:24063017)
• new variants in genes such as COCH is associated with nonsyndromic deafness and vestibular dysfunction. (PMID:24275721)
• A new phenotypic and characteristic radiologic feature of DFNA9 has been discovered. (PMID:24662630)
• prominent in the incudomalleal joint, incudostapedial joint, and the pars tensa of the tympanic membrane (PMID:25049087)
• This is the first report showing failure of mutant cochlin transport through the secretory pathway, abolishment of cochlin secretion, and formation and retention of dimers and large multimeric intracellular aggregates (PMID:25230692)
• Targeted exon resequencing of selected genes using next-generation sequencing identified 3 COCH (one known, two novel) mutations in a cohort of hearing loss patients in Japan. (PMID:25780252)
• the impaired post-translational cleavage of cochlin mutants may be associated with pathological mechanisms underlying DFNA9-related sensorineural hearing loss. (PMID:26256111)
• This family is the first case of a truncating COCH variant and supports the hypothesis that COCH haploinsufficiency is not the cause of hearing loss in humans. (PMID:26631968)
• Distinct vestibular phenotypes depending on the location of COCH mutations were demonstrated, and this study correlates a genotype of p.G38D in COCH to the phenotype of bilateral total vestibular loss, therefore expanding the vestibular phenotypic spectrum of DFNA9 to range from bilateral vestibular loss without episodic vertigo to MD-like features with devastating episodic vertigo (PMID:26758463)
• This study showed that Mendelian sensorineural hearing loss exhibits vestibular dysfunction, including DFNA9, DFNA11, DFNA15 and DFNA28. (PMID:27083884)
• COCH expression is significantly downregulated in human masticatory mucosa during wound healing (PMID:28005267)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	coch	ENSDARG00000024032
mus_musculus	Coch	ENSMUSG00000020953
rattus_norvegicus	Coch	ENSRNOG00000005286

Paralogs (12): COL12A1 (ENSG00000111799), MATN4 (ENSG00000124159), MATN3 (ENSG00000132031), MATN2 (ENSG00000132561), MATN1 (ENSG00000162510), COL6A3 (ENSG00000163359), VWA2 (ENSG00000165816), COL6A5 (ENSG00000172752), VWA1 (ENSG00000179403), COL14A1 (ENSG00000187955), VIT (ENSG00000205221), COL6A6 (ENSG00000206384)

Protein

Protein identifiers

Cochlin — O43405 (reviewed: O43405)

Alternative names: COCH-5B2

All UniProt accessions (9): O43405, A0A2R8Y3T0, A0A2U3TZE7, G3V4C4, G3V5G6, G3V5V4, G3V5X3, H0YJJ0, H0YJW4

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the control of cell shape and motility in the trabecular meshwork.

Subunit / interactions. Monomer. May form homodimer. Interacts with type II collagen. Interacts with SLC44A2. Interacts with ANXA2.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in inner ear structures; the cochlea and the vestibule.

Post-translational modifications. N-glycosylated. A 50 kDa form is created by proteolytic cleavage.

Disease relevance. Deafness, autosomal dominant, 9 (DFNA9) [MIM:601369] A form of non-syndromic hearing loss characterized by onset in the fourth or fifth decade of life and initially involves the high frequencies. Hearing loss is progressive and usually complete by the sixth decade. In addition to cochlear involvement, DFNA9 patients also exhibit a spectrum of vestibular dysfunctions. Penetrance of the vestibular symptoms is often incomplete, and some patients are minimally affected, whereas others suffer from severe balance disturbances and episodes of vertigo. Affected individuals have mucopolysaccharide depositions in the channels of the cochlear and vestibular nerves. These depositions apparently cause strangulation and degeneration of dendritic fibers. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal recessive, 110 (DFNB110) [MIM:618094] A form of non-syndromic, sensorineural deafness characterized by prelingual 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. DFNB110 affected individuals additionally exhibit mild, age-dependent vestibular dysfunction. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
O43405-1	1	yes
O43405-2	2

RefSeq proteins (3): NP_001128530, NP_001334649, NP_004077* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002035	VWF_A	Domain
IPR004043	LCCL	Domain
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR036609	LCCL_sf	Homologous_superfamily
IPR050525	ECM_Assembly_Org	Family

Pfam: PF00092, PF03815

UniProt features (41 total): sequence variant 21, strand 6, domain 3, disulfide bond 2, glycosylation site 2, signal peptide 1, chain 1, splice variant 1, turn 1, helix 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1JBI	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43405-F1	85.93	0.61

Functional residue map

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

Disulfide bonds (2): 54–74, 34–50

Glycosylation sites (2): 100, 221

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 187 (showing top): LEE_NEURAL_CREST_STEM_CELL_DN, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, MODULE_255, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, TTTGTAG_MIR520D, VICENT_METASTASIS_UP, MODULE_317, AAAYRNCTG_UNKNOWN, chr14q12, MORF_ZNF10, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, SAMOLS_TARGETS_OF_KHSV_MIRNAS_UP, MODULE_206, MORF_EPHA7, GOBP_SENSORY_PERCEPTION

GO Biological Process (2): sensory perception of sound (GO:0007605), regulation of cell shape (GO:0008360)

GO Molecular Function (2): collagen binding (GO:0005518), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), extracellular matrix (GO:0031012)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory perception of mechanical stimulus	1
regulation of cell morphogenesis	1
regulation of biological quality	1
protein-containing complex binding	1
binding	1
cellular anatomical structure	1
external encapsulating structure	1

Protein interactions and networks

STRING

1106 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
COCH	TECTB	Q96PL2	902
COCH	SLC22A17	Q8WUG5	830
COCH	STXBP6	Q8NFX7	825
COCH	SLC44A2	Q8IWA5	817
COCH	TECTA	O75443	783
COCH	CALB1	P05937	653
COCH	BCHE	P06276	641
COCH	KCNK2	O95069	639
COCH	KCNK3	O14649	526
COCH	OTOA	Q7RTW8	512
COCH	COL2A1	P02458	507
COCH	ANXA2	P07355	488
COCH	OTOS	Q8NHW6	479
COCH	GJB2	P29033	458
COCH	FN1	P02751	451

IntAct

49 interactions, top by confidence:

A	B	Type	Score
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
OS9	AGRN	psi-mi:“MI:0914”(association)	0.530
VIT	COCH	psi-mi:“MI:0914”(association)	0.530
TRAC	COCH	psi-mi:“MI:0914”(association)	0.530
SERPINA6	COCH	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
INSL5	COCH	psi-mi:“MI:0914”(association)	0.530
COCH	COL1A1	psi-mi:“MI:0407”(direct interaction)	0.440
COL2A1	COCH	psi-mi:“MI:0407”(direct interaction)	0.440
COL4A1	COCH	psi-mi:“MI:0407”(direct interaction)	0.440
TNIP1	COCH	psi-mi:“MI:0914”(association)	0.350
INSL5	LAMA5	psi-mi:“MI:0914”(association)	0.350
TMEM25	FUZ	psi-mi:“MI:0914”(association)	0.350
PTCH1	PLXNB2	psi-mi:“MI:0914”(association)	0.350
SCARA3	DEGS1	psi-mi:“MI:0914”(association)	0.350
IDS	COCH	psi-mi:“MI:0914”(association)	0.350
SIAE	COCH	psi-mi:“MI:0914”(association)	0.350
INSR	HAX1	psi-mi:“MI:0914”(association)	0.350
NTRK3	ILVBL	psi-mi:“MI:0914”(association)	0.350
TYRO3	HAX1	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CDH23	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
SCGB2A2	RTL8C	psi-mi:“MI:0914”(association)	0.350

BioGRID (71): COCH (Affinity Capture-MS), COCH (Affinity Capture-MS), COCH (Affinity Capture-MS), COCH (Affinity Capture-MS), COCH (Affinity Capture-MS), COCH (Affinity Capture-MS), COCH (Affinity Capture-MS), COCH (Synthetic Growth Defect), COCH (Biochemical Activity), COCH (Affinity Capture-MS), COCH (Affinity Capture-MS), COCH (Affinity Capture-MS), COCH (Affinity Capture-MS), COCH (Affinity Capture-MS), COCH (Affinity Capture-MS)

ESM2 similar proteins: O15537, O35276, O35375, O35474, O42163, O42596, O43405, O43854, O60242, O60462, O75077, O75882, O95970, P15209, P21956, P24786, P26012, P51641, P70490, P79385, P84552, Q03351, Q16288, Q16620, Q1EGL2, Q5EA64, Q5IS37, Q5IS82, Q5R7K9, Q5R945, Q5VV63, Q62507, Q63604, Q63769, Q6A051, Q6IS24, Q7TT15, Q80ZF8, Q91044, Q91987

Diamond homologs: A0A1D5NSM8, A0JNA2, A2AVA0, A2AX52, D3YXF5, O02839, O19063, O35764, O43405, O70340, O76536, O89029, O95502, O96530, P02741, P02743, P06205, P06206, P06207, P06681, P07202, P07629, P08607, P09871, P0C6B8, P10643, P12246, P13944, P14151, P14847, P15697, P18337, P23680, P32018, P47970, P47971, P47972, P48199, P49254, P49262

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 55 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Non-integrin membrane-ECM interactions	5	21.4×	3e-04
ECM proteoglycans	5	20.9×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	11
Uncertain significance	161
Likely benign	64
Benign	40

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1185584	NM_004086.3(COCH):c.1624T>C (p.Cys542Arg)	Pathogenic
1451749	NM_004086.3(COCH):c.433del (p.Thr145fs)	Pathogenic
2144768	NM_004086.3(COCH):c.1139_1142dup (p.Ser381delinsArgTer)	Pathogenic
236036	NM_004086.3(COCH):c.1159C>T (p.Leu387Phe)	Pathogenic
2736106	NM_004086.3(COCH):c.362T>C (p.Phe121Ser)	Pathogenic
3339911	NM_004086.3(COCH):c.1046_1049del (p.Lys349fs)	Pathogenic
3376726	NM_004086.3(COCH):c.1273del (p.Ser425fs)	Pathogenic
3675020	NM_004086.3(COCH):c.302_303del (p.Tyr101fs)	Pathogenic
4713600	NM_004086.3(COCH):c.1111_1114dup (p.Ile372fs)	Pathogenic
4740428	NM_004086.3(COCH):c.787dup (p.Arg263fs)	Pathogenic
4762958	NM_004086.3(COCH):c.937C>T (p.Gln313Ter)	Pathogenic
6608	NM_004086.3(COCH):c.197T>G (p.Val66Gly)	Pathogenic
6611	NM_004086.3(COCH):c.151C>T (p.Pro51Ser)	Pathogenic
6612	NM_004086.3(COCH):c.326T>A (p.Ile109Asn)	Pathogenic
6614	NM_004086.3(COCH):c.1625G>T (p.Cys542Phe)	Pathogenic
870100	NM_004086.3(COCH):c.984_985dup (p.Phe329fs)	Pathogenic
2581793	NM_004086.3(COCH):c.1196_1213del (p.Ile399_Ala404del)	Likely pathogenic
3601050	NM_004086.3(COCH):c.1412T>G (p.Val471Gly)	Likely pathogenic
3601051	NM_004086.3(COCH):c.1547C>A (p.Pro516Gln)	Likely pathogenic
3601053	NM_004086.3(COCH):c.152C>A (p.Pro51Gln)	Likely pathogenic
3601054	NM_004086.3(COCH):c.340C>G (p.Leu114Val)	Likely pathogenic
3620741	NM_004086.3(COCH):c.260G>A (p.Gly87Glu)	Likely pathogenic
431458	NM_004086.3(COCH):c.292C>T (p.Arg98Ter)	Likely pathogenic
4813859	NM_004086.3(COCH):c.116T>A (p.Leu39Ter)	Likely pathogenic
504332	NM_004086.3(COCH):c.1446_1452delinsTGGA (p.Gln483del)	Likely pathogenic
517362	NM_004086.3(COCH):c.260G>C (p.Gly87Ala)	Likely pathogenic
869458	NM_004086.3(COCH):c.1053C>A (p.Cys351Ter)	Likely pathogenic

SpliceAI

1667 predictions. Top by Δscore:

Variant	Effect	Δscore
14:30877570:A:AG	acceptor_gain	1.0000
14:30877571:G:GG	acceptor_gain	1.0000
14:30878810:GGGGA:G	acceptor_gain	1.0000
14:30878945:G:GG	donor_gain	1.0000
14:30880445:A:AG	acceptor_gain	1.0000
14:30880450:A:AG	acceptor_gain	1.0000
14:30880450:AG:A	acceptor_gain	1.0000
14:30880451:G:GT	acceptor_gain	1.0000
14:30880451:GG:G	acceptor_gain	1.0000
14:30880451:GGT:G	acceptor_gain	1.0000
14:30880451:GGTA:G	acceptor_gain	1.0000
14:30880451:GGTAA:G	acceptor_gain	1.0000
14:30880497:G:GG	donor_gain	1.0000
14:30880498:T:G	donor_loss	1.0000
14:30884551:A:AG	acceptor_gain	1.0000
14:30884552:G:GG	acceptor_gain	1.0000
14:30884552:GT:G	acceptor_gain	1.0000
14:30885386:A:AG	acceptor_gain	1.0000
14:30885387:A:G	acceptor_gain	1.0000
14:30885390:TTAG:T	acceptor_loss	1.0000
14:30885391:TA:T	acceptor_loss	1.0000
14:30885393:GGAA:G	acceptor_gain	1.0000
14:30885393:GGAAA:G	acceptor_gain	1.0000
14:30885600:G:GT	donor_gain	1.0000
14:30886310:CAGGT:C	donor_loss	1.0000
14:30886311:AGGT:A	donor_loss	1.0000
14:30886312:GGTAA:G	donor_loss	1.0000
14:30886313:G:A	donor_loss	1.0000
14:30886314:T:A	donor_loss	1.0000
14:30877567:TTCA:T	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000039482 (14:30886873 G>A,C), RS1000138713 (14:30888025 G>C), RS1000235773 (14:30892246 C>G,T), RS1000278208 (14:30882845 C>A), RS1000344378 (14:30877080 A>C,G), RS1000502630 (14:30890734 C>A), RS1000573190 (14:30891005 C>G), RS1000620047 (14:30881585 T>C), RS1000800387 (14:30876893 G>A,C), RS1000931502 (14:30893403 C>T), RS1001162616 (14:30887798 A>T), RS1001186634 (14:30876415 G>C,T), RS1001538811 (14:30888469 T>C), RS1001658292 (14:30888834 G>A), RS1001676832 (14:30882286 C>T)

Disease associations

OMIM: gene MIM:603196 | disease phenotypes: MIM:601369, MIM:276900, MIM:618094

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss 9	Strong	Autosomal dominant
hearing loss, autosomal recessive 110	Strong	Autosomal recessive
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AD

Mondo (6): autosomal dominant nonsyndromic hearing loss 9 (MONDO:0011058), Usher syndrome (MONDO:0019501), hearing loss disorder (MONDO:0005365), hearing loss, autosomal recessive 110 (MONDO:0054860), nonsyndromic genetic hearing loss (MONDO:0019497), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (4): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Usher syndrome (Orphanet:886), Rare non-syndromic genetic deafness (Orphanet:87884), Rare genetic deafness (Orphanet:96210)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000360	Tinnitus
HP:0000407	Sensorineural hearing impairment
HP:0001751	Abnormal vestibular function
HP:0002321	Vertigo
HP:0003577	Congenital onset
HP:0003676	Progressive
HP:0005102	Cochlear degeneration
HP:0008596	Postlingual sensorineural hearing impairment
HP:0009591	Abnormal vestibulocochlear nerve morphology
HP:0011462	Young adult onset

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST003542_117	Night sleep phenotypes	3.000000e-06
GCST004599_161	Mean platelet volume	2.000000e-09
GCST006585_2713	Blood protein levels	2.000000e-38
GCST010703_231	Brain morphology (MOSTest)	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
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
C563335	Deafness, Autosomal Dominant 9 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1045644	COCH		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	3
Cisplatin	increases expression, decreases expression	3
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Oxygen	decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
chloroacetaldehyde	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	affects methylation	1
cobaltous chloride	decreases expression	1
ochratoxin A	increases acetylation, increases expression	1
nickel sulfate	decreases expression	1
cupric oxide	decreases expression	1
CGP 52608	affects binding, increases reaction	1
adefovir dipivoxil	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
belinostat	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
NSC 689534	affects binding, decreases expression	1
Rosiglitazone	decreases expression	1
Sunitinib	decreases expression	1

Clinical trials (associated diseases)

300 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
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
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
NCT02065011	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Determine the Long-Term Safety, Tolerability and Biological Activity of SAR421869 in Patients With Usher Syndrome Type 1B
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
NCT03707756	Not specified	WITHDRAWN	Systematic Review of Phenotypical Characteristics of P51S COCH Mutation
NCT03716908	Not specified	RECRUITING	Genotype-phenotype Correlation Study of Presymptomatic and Symptomatic DFNA9 Patients
NCT04066270	Not specified	UNKNOWN	Inventory of Radiological and Vestibular Function in Cochlear Implant Candidates
NCT04070937	Not specified	RECRUITING	Correlation of Radiological Lesions With Vestibular Function in Patients With Bilateral Vestibulopathy
NCT04331015	Not specified	COMPLETED	Artificial Intelligence in Diagnosis of DFNA9
NCT07091071	Not specified	COMPLETED	Evaluation of the CochSyn Device in Clinical Practice
NCT01505062	PHASE1/PHASE2	TERMINATED	Study of SAR421869 in Participants With Retinitis Pigmentosa Associated With Usher Syndrome Type 1B