CLRN2

Chr 4AR

clarin 2

Also known as: DFNB117

NCBI Gene: 645104 ENSG00000249581 UniProt: A0PK11 OMIM: 618988

CLRN2 encodes clarin-2, a four-transmembrane domain protein required for normal organization and maintenance of stereocilia bundles and mechano-electrical transduction in the inner ear. Mutations cause autosomal recessive hearing loss. The gene is not highly constrained against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene belongs to the clarin family of genes. The clarins appear to belong to a large superfamily of small integral membrane glycoproteins with four transmembrane domains. The exact function of this gene is unknown. [provided by RefSeq, Oct 2008]

OMIM ResearchGenerating clinical summary…

GOFmechanismARLOEUF 1.611 OMIM phenotype

Clinical Summary— CLRN2

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARModerate

Moderate evidence — consider for supplementary testing

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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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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 37 VUS of 44 total submissions

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?

1.61LOEUF

pLI 0.000

Z-score 0.18

OE 0.94 (0.56–1.61)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.26Z-score

OE missense 0.94 (0.82–1.08)

136 obs / 144.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.94 (0.56–1.61)

0≤0.351.4

Missense OE?0.94 (0.82–1.08)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 9 / 9.6Missense obs/exp: 136 / 144.9Syn Z: -0.77

This gene — mechanism propensity

0.5081th %ile

GOF

0.7029th %ile

LOF

0.2871th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

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.

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

ClinVar Variant Classifications

44 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS37

Likely Benign4

Benign1

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	1	1
Likely Pathogenic	0	0
VUS	37	37
Likely Benign	4	4
Benign	1	1
Total	43	43

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

43 pathogenic / likely-pathogenic (of 54) ClinVar copy-number / structural variants overlap CLRN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →