CIB2

Chr 15AR

calcium and integrin binding family member 2

Also known as: DFNB48, KIP2, USH1J

NCBI Gene: 10518ENSG00000136425UniProt: O75838

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]

Primary Disease Associations & Inheritance

Deafness, autosomal recessive 48MIM #609439
AR
UniProtUsher syndrome 1J
270
ClinVar variants
46
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— CIB2
🧬
Gene-Disease Validity (ClinGen)
Usher syndrome type 1 · ARRefuted

Refuted — evidence has disproved this relationship

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 92 VUS of 270 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.52Z-score
OE missense 0.86 (0.73–1.02)
98 obs / 113.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.55 (0.30–1.09)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.73–1.02)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93
0≤1.21.6
LoF obs/exp: 6 / 10.9Missense obs/exp: 98 / 113.5Syn Z: 0.38

ClinVar Variant Classifications

270 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35
Likely Pathogenic11
VUS92
Likely Benign102
Benign23
Conflicting7
35
Pathogenic
11
Likely Pathogenic
92
VUS
102
Likely Benign
23
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
2
22
0
35
Likely Pathogenic
4
3
4
0
11
VUS
0
77
13
2
92
Likely Benign
0
4
54
44
102
Benign
0
0
20
3
23
Conflicting
—7
Total158611349270

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

View in ClinVar →

Protein Context — Lollipop Plot

CIB2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

CIB2-related nonsyndromic deafness

strong
ARUndeterminedAltered Gene Product Structure
Dev. DisordersEar
G2P ↗
missense variantinframe deletioninframe insertion

CIB2-related Usher syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Deafness, autosomal recessive 48

MIM #609439

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CIB2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Global genetic insight contributed by consanguineous Pakistani families segregating hearing loss.
Richard EM et al.·Hum Mutat
2019
Structural insights into calcium-dependent CIB2-TMC1 interaction in hair cell mechanotransduction.
Li Y et al.·Commun Biol
2025
Variants in CIB2 cause DFNB48 and not USH1J.
Booth KT et al.·Clin Genet
2018
Genetic Testing of Non-familial Deaf Patients for CIB2 and GJB2 Mutations: Phenotype and Genetic Counselling.
Shaikh H et al.·Biochem Genet
2017Clinical trial
Novel and recurrent CIB2 variants, associated with nonsyndromic deafness, do not affect calcium buffering and localization in hair cells.
Seco CZ et al.·Eur J Hum Genet
2016
A large-scale screening identified in USH2A gene the P3272L founder pathogenic variant explaining familial Usher syndrome in Sardinia, Italy.
Serra R et al.·BMC Ophthalmol
2024
Genetic influence of the brain imaging phenotypes, brain and cerebrospinal fluid metabolites and brain genes on migraine subtypes: a Mendelian randomization and multi-omics study.
Zhang PA et al.·J Headache Pain
2025
PDZD7 and hearing loss: More than just a modifier.
Booth KT et al.·Am J Med Genet A
2015
Autosomal recessive non-syndromic hearing loss genes in Pakistan during the previous three decades.
Shadab M et al.·J Cell Mol Med
2024Review
Novel pathogenic mutations and further evidence for clinical relevance of genes and variants causing hearing impairment in Tunisian population.
Souissi A et al.·J Adv Res
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools