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CIB2
calcium and integrin binding family member 2
CIB2 is located on the long (q) arm of chromosome 15, at band 15q25.1. Arm ratio per GRCh38 - banding schematic.
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Overview
CIB2 (calcium and integrin binding family member 2) is located on chromosome 15q25.1 and encodes a 187-amino-acid protein that plays a vital role in auditory function. The protein belongs to a family of calcium-binding molecules that regulate various cellular processes, but CIB2 has evolved a specialised function in the sensory hair cells of the cochlea. These hair cells convert mechanical sound waves into electrical impulses that the brain interprets as sound. When CIB2 function is compromised by pathogenic variants, individuals typically experience non-syndromic hearing loss, meaning deafness occurs without additional features affecting other organ systems. The gene is recognised on UK clinical panels for monogenic hearing loss, underscoring its importance in diagnosing inherited forms of deafness.
What the gene does
The CIB2 protein functions as a calcium sensor within cochlear hair cells, where it participates in mechanotransduction-the process by which mechanical stimuli are converted into biochemical signals. Hair cells possess tiny hair-like projections called stereocilia that deflect in response to sound vibrations. This deflection opens mechanosensitive ion channels, allowing calcium ions to flow into the cell and trigger the release of neurotransmitters that signal the auditory nerve. CIB2 localises to the mechanotransduction complex at the tips of stereocilia, where it appears to regulate the function and stability of these ion channels. By binding calcium, CIB2 may help modulate channel activity in response to changing calcium concentrations, ensuring that hair cells maintain proper sensitivity across a range of sound intensities. Loss of CIB2 disrupts this finely tuned system, leading to progressive or congenital hearing impairment. The protein's role appears highly specific to auditory tissue, which explains why pathogenic variants typically affect hearing without causing widespread developmental abnormalities.
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Chromosome location
CIB2 is located on the long arm of chromosome 15 at cytogenetic band 15q25.1. This region of chromosome 15 contains several genes involved in sensory and developmental processes. The precise genomic coordinates and exon structure contribute to the gene's expression pattern, which is enriched in inner ear tissues during development and throughout life.
Protein structure
The CIB2 protein is organised around three EF-hand calcium-binding motifs, which are the defining structural features of this protein family. EF-hand 1 spans amino acids 66 to 101, EF-hand 2 extends from amino acids 103 to 138, and EF-hand 3 occupies positions 144 to 179. Each EF-hand consists of a helix-loop-helix structure that coordinates calcium ions through negatively charged residues in the loop region. These three tandem EF-hands enable CIB2 to undergo conformational changes upon calcium binding, which likely modulates its interactions with other proteins in the mechanotransduction complex. The compact arrangement of these domains within the 187-amino-acid sequence allows CIB2 to function as a dynamic calcium sensor in the confined space of the stereociliary tip.
Key variants
Pathogenic variants in CIB2 have been identified across the gene's coding sequence, with many affecting the EF-hand domains that are essential for calcium binding. Variants may disrupt the protein's ability to coordinate calcium ions, alter its stability, or interfere with its localisation to stereocilia. Both homozygous and compound heterozygous variants have been reported in individuals with autosomal recessive non-syndromic hearing loss, whilst certain variants have also been associated with dominant forms of deafness depending on their functional impact.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.196C>T | p.Arg66Trp | Pathogenic/Likely pathogenic | ★★☆☆ | Retinal dystrophy |
c.300_309del | p.Glu100fs | Pathogenic/Likely pathogenic | ★★☆☆ | Rare genetic deafness |
c.97C>T | p.Arg33Ter | Pathogenic | ★★☆☆ | Usher syndrome |
c.175del | p.Ile59fs | Pathogenic | ★☆☆☆ | Autosomal recessive nonsyndromic hearing loss 48 |
c.280_281del | p.Met94fs | Pathogenic | ★☆☆☆ | not provided |
c.286del | p.Ser96fs | Pathogenic | ★☆☆☆ | Autosomal recessive nonsyndromic hearing loss 48 |
c.375_381del | p.Lys125fs | Pathogenic | ★☆☆☆ | Autosomal recessive nonsyndromic hearing loss 48 |
c.384_385insT | p.Glu129Ter | Pathogenic | ★☆☆☆ | Autosomal recessive nonsyndromic hearing loss 48 |
c.530del | p.Pro177fs | Pathogenic | ★☆☆☆ | Autosomal recessive nonsyndromic hearing loss 48 |
c.531del | p.Asp178fs | Pathogenic | ★☆☆☆ | Autosomal recessive nonsyndromic hearing loss 48 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in CIB2 are primarily associated with non-syndromic hearing loss, where deafness is the sole clinical manifestation. The severity and age of onset can vary: some individuals present with profound congenital deafness, whilst others experience progressive hearing loss beginning in childhood or early adulthood. The inheritance pattern is typically autosomal recessive, meaning affected individuals carry pathogenic variants on both copies of the gene. The absence of extra-auditory features distinguishes CIB2-related hearing loss from syndromic forms of deafness that affect multiple organ systems.
No disease links recorded for this gene in our reference set.
UK clinical status
CIB2 is included on the NHS Genomic Medicine Service panel for monogenic hearing loss with a green classification and R67 gene confidence level, indicating strong evidence supporting its role in inherited deafness. The gene also appears in the DDG2P (Developmental Disorders Genotype-to-Phenotype) database with green status, reflecting robust gene-disease validity. These panel memberships mean that CIB2 is routinely analysed when genetic testing is undertaken for unexplained hearing loss through NHS pathways, helping to identify the underlying cause in affected families.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern is associated with CIB2 variants?
Most CIB2-related hearing loss follows an autosomal recessive pattern, meaning an individual must inherit pathogenic variants from both parents to be affected. Some variants have been reported with dominant effects, where a single pathogenic variant can cause hearing loss.
Does CIB2-related hearing loss affect other parts of the body?
CIB2 variants typically cause non-syndromic hearing loss, meaning deafness occurs without additional features affecting vision, development, or other organ systems. The protein's function appears highly specific to the inner ear.
Is CIB2 tested on the NHS for hearing loss?
Yes, CIB2 is included on the NHS Genomic Medicine Service panel for monogenic hearing loss with green gene status, meaning it is routinely analysed during genetic testing for unexplained deafness through NHS pathways.