CIB2

Chr 15AR

calcium and integrin binding family member 2

Also known as: DFNB48, KIP2, USH1J

NCBI Gene: 10518 ENSG00000136425 UniProt: O75838 OMIM: 605564

The protein encoded by CIB2 is a calcium-binding regulatory protein that acts as an auxiliary subunit of mechanotransduction channels in hair cells and is essential for hearing, while also playing a critical role in photoreceptor cell maintenance. Mutations cause autosomal recessive nonsyndromic deafness (DFNB48) and Usher syndrome type 1J, which combines congenital profound hearing loss with progressive vision loss due to retinitis pigmentosa. The gene shows relatively low constraint against loss-of-function variants (pLI 0.001, LOEUF 1.09), but mutations consistently affect both auditory and visual function when present.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is similar to that of KIP/CIB, calcineurin B, and calmodulin. The encoded protein is a calcium-binding regulatory protein that interacts with DNA-dependent protein kinase catalytic subunits (DNA-PKcs), and it is involved in photoreceptor cell maintenance. Mutations in this gene cause deafness, autosomal recessive, 48 (DFNB48), and also Usher syndrome 1J (USH1J). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 48MIM #609439

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.09

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — CIB2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.09LOEUF

pLI 0.001

Z-score 1.37

OE 0.55 (0.30–1.09)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.52Z-score

OE missense 0.86 (0.73–1.02)

98 obs / 113.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.30–1.09)

0≤0.351.4

Missense OE?0.86 (0.73–1.02)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 6 / 10.9Missense obs/exp: 98 / 113.5Syn Z: 0.38

Background carrier burden — how many people carry a rare variant somewhere in CIB2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

354 rare PASS variants

Rare truncating (LoF)

1 in 1,300

60 rare PASS variants

Rare synonymous (reference)

1 in 570

106 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CIB2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 160	1 in 1,200
South Asian	~43k	1 in 82	1 in 2,700
Remaining (unassigned)	~30k	1 in 110	1 in 3,200
European (Finnish)	~27k	1 in 470	≈ 1 in 22,000
Admixed American	~22k	1 in 130	1 in 3,600
African / African American	~21k	1 in 92	1 in 1,500
East Asian	~20k	1 in 190	≈ 1 in 4,000
Ashkenazi Jewish	~13k	1 in 560	none seen
Middle Eastern	~2,884	1 in 99	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 5 of 6 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 6.? see exons ↓