COCH

protein-coding

cochlin

Gene summary

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. [provided by RefSeq, Oct 2008]

Previous symbols:

DFNA31
DFNA9

MANE transcript

NM_004086.3

Inheritance

AR, AD

ClinVar variants

P:42U:164B:55

Top phenotype

Deafness, autosomal recessive 110

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr14:30,874,514-30,895,065

External References & Databases

Ensembl (ENSG00000100473)

Transcript & Mutation Effects

hg38 • Region Span ~20.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal recessive 110STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054860

Submitter: Labcorp Genetics (formerly Invitae)

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The COCH gene has been associated with autosomal dominant nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 12/28/2017. This association was made using case-level data only. At least 11 missense variants have been reported in humans. COCH was first associated with this disease in humans as early as 1998 (Robertson et al.). Association is seen in at least 13 probands in 11 publications (16151338, 28116169, 28099493, 9806553, 17561763, 21046548, 26256111, 22931125, 22610276, 18312449, 28733840). Variants in this gene segregated with disease in >50 additional family members. This gene-disease association is supported by a knock-in mouse model with the p.Gly88Glu variant, expression in human postmortem temporal bones and chicken cochlea, as well as approved localization and Western blot assessment. In summary, COCH is definitively associated with autosomal dominant nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 1/5/2018.

autosomal dominant nonsyndromic hearing loss 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011058

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: LiferaOmics

Genetic evidence – Published: PMID: 29449721 reports 2 affected brothers (single consanguineous family) with homozygous nonsense COCH c.292C>T; p.(Arg98Ter); parents heterozygous; autosomal recessive inheritance. Case-level (biallelic predicted null; consanguinity downgrade) = 1.0 (1.5 − 0.5); segregation (1 additional affected sibling) = 0.5; case-control = 0. Family total = 1.5 PMID: 32939038 reports 3 affected individuals from one consanguineous pedigree with homozygous frameshift COCH loss-of-function variant; segregation demonstrated within family. Case-level (biallelic predicted null; consanguinity downgrade) = 1.0 (1.5 − 0.5); segregation (2 additional affected relatives) = 1.0 (0.5 + 0.5); case-control = 0. Family total = 2.0 PMID: 32562050 reports four independent families with AR COCH-related hearing loss: A) Consanguineous family with 3 affected, homozygous nonsense variant; case-level (predicted null; consanguinity downgrade) = 1.0; segregation (2 additional affected) = 1.0; subtotal = 2.0 B) Non-consanguineous family with 1 affected carrying biallelic LoF alleles (nonsense + splice-altering); case-level (predicted null, no downgrade) = 1.5; segregation = 0; subtotal = 1.5 C) Consanguineous family with 1 affected homozygous missense (non-pLoF); case-level (AR “other variant” default) = 0.5; segregation = 0; subtotal = 0.1 D) Consanguineous family with 1 affected homozygous splice-altering/in-frame allele shown functionally to create null effect; case-level (predicted null; consanguinity downgrade) = 1.0; segregation = 0; subtotal = 1.0 PMID: 32562050 total = 5.0; case-control = 0 Published genetic total = 8.1 / 12 Genetic evidence – our case: 1 proband (15-year-old; consanguinity) with hearing loss and homozygous frameshift COCH NM_001347720.2:c.1483_1484del; p.(Val495ProfsTer18) (predicted null); no additional genotyped affected relatives; no segregation or case-control data. Case-level (biallelic predicted null; consanguinity downgrade) = 1.0 (1.5 − 0.5); segregation = 0; case-control = 0 our case contribution = 1.0 / 12 Total genetic evidence = 9.1 / 12 Experimental evidence – Published: PMID: 32562050 demonstrates minigene splicing assays showing that non-truncating variants cause aberrant splicing leading to frameshift/null alleles (+1.0 functional alteration evidence) PMID: 32939038 shows marked reduction/absence of cochlin translation for homozygous LoF alleles in cell-based assays (+1.0 functional evidence) Experimental total = 2.0 / 6 Overall score = 11.1

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 110AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

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

Refs: 8817345; 9806553; 10400989; 14512963; 16261627; 18312449; 19161137; 20447147; 21046548; 21052762; 21774451; 22610276; 22931125; 29449721

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COCH variants in ClinVar

14 Conditions Cataloged

not providedTotal: 232

Autosomal dominant nonsyndromic hearing loss 9Total: 58

Inborn genetic diseasesTotal: 56

not specifiedTotal: 50

COCH-related disorderTotal: 38

Hearing loss, autosomal recessive 110Total: 13

Nonsyndromic genetic hearing lossTotal: 11

Hearing impairmentTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004086.3. 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			5 clinvar	39 clinvar	2 clinvar	46
missense	11 clinvar	16 clinvar	153 clinvar	12 clinvar	2 clinvar	194
nonsense	1 clinvar	5 clinvar	3 clinvar			9
start loss						0
frameshift	8 clinvar		2 clinvar			10
splice donor/acceptor (+/-2bp)		1 clinvar	1 clinvar			2
Total	20	22	164	51	4	261

Highest pathogenic variant AF is 0.00005328152

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 40 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004086.3	RefSeq	NP_004077.1	11	MANE Select
ENST00000396618.9	Ensembl	ENSP00000379862.3	11	MANE Select
NM_001135058.2	RefSeq	NP_001128530.1	11	Standard
NM_001347720.2	RefSeq	NP_001334649.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

growth plate cartilage chondrocyte morphogenesis
sensory perception of sound
regulation of cell shape
defense response to bacterium
positive regulation of innate immune response

Molecular Function

protein binding
collagen binding

Cellular Component

extracellular space
extracellular matrix
collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000396618
Coding exons: 11
Length: 20552
Individuals with no LoFs: 125687
Homozygous LoFs: 0
Heterozygous LoFs: 61
Defined: 125748
p: 0.000243

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.676	264	297	0.890	0.0000148	3612
Missense (PolyPhen)		99	112.74	0.87812		1481
Synonymous	-0.900	118	106	1.11	0.00000536	1088
Loss of Function	1.90	15	25.3	0.593	0.00000143	284

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00060	0.00060	rare
East Asian	0.00087	0.00087	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00026	0.00023	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the control of cell shape and motility in the trabecular meshwork. {ECO:0000269|PubMed:21886777}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:10400989, ECO:0000269|PubMed:11295836, ECO:0000269|PubMed:12928864, ECO:0000269|PubMed:14512963, ECO:0000269|PubMed:16835921, ECO:0000269|PubMed:17561763, ECO:0000269|PubMed:18312449, ECO:0000269|PubMed:22610276, ECO:0000269|PubMed:22931125, ECO:0000269|PubMed:23993205, ECO:0000269|PubMed:25388789, ECO:0000269|PubMed:9806553, ECO:0000269|PubMed:9931344}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.132

Intolerance Scores

LoFtool: 0.238
RVIS EVS: 0.29
RVIS percentile EVS: 71.5

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.545

Gene Damage Prediction

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