COCH

Chr 14ARAD

cochlin

Also known as: COCH-5B2, COCH5B2, DFNA9, DFNB110

NCBI Gene: 1690 ENSG00000100473 UniProt: O43405 OMIM: 603196

Cochlin is a secreted protein found in the inner ear that controls cell shape and motility in the trabecular meshwork and is expressed in spindle-shaped cells along auditory nerve fibers. Mutations cause autosomal dominant nonsyndromic sensorineural hearing loss (DFNA9) and possibly autosomal recessive deafness. The gene shows very low constraint against loss-of-function variants (pLI near zero), suggesting tolerance to complete gene loss.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAR/ADLOEUF 0.912 OMIM phenotypes

Clinical Summary— COCH

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.91LOEUF

pLI 0.000

Z-score 1.90

OE 0.59 (0.40–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

0.68Z-score

OE missense 0.89 (0.80–0.98)

264 obs / 296.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.59 (0.40–0.91)

0≤0.351.4

Missense OE0.89 (0.80–0.98)

0≤0.61.4

Synonymous OE1.11

0≤1.21.6

LoF obs/exp: 15 / 25.3Missense obs/exp: 264 / 296.8Syn Z: -0.90

0.7229th %ile

GOF

0.76top 25%

LOF

0.3068th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function, dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

LOF1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNIn the case of DFNA9, stable detection of the mutant COCH transcript is consistent with the hypothesis of a dominant-negative effect of the mutation in DFNA9 pathology rather than haploinsufficiency of cochliPMID:16481359

GOFMakishima et al. (2005) concluded that DFNA9 may not be caused by COCH haploinsufficiency but by a dominant-negative or gain-of-function effect in nonsensory regions of the inner ear.PMID:16078052

LOFA novel frameshift variant of COCH supports the hypothesis that haploinsufficiency is not a cause of autosomal dominant nonsyndromic deafness 9.PMID:26631968

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.