CIB2

Summary

CIB2 (calcium and integrin binding family member 2, HGNC:24579) is a protein-coding gene on chromosome 15q25.1, encoding Calcium and integrin-binding family member 2 (O75838). Calcium- and integrin-binding protein that plays a role in intracellular calcium homeostasis.

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.

Source: NCBI Gene 10518 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 250 total — 17 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 18
• MANE Select transcript: NM_006383

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24579
Approved symbol	CIB2
Name	calcium and integrin binding family member 2
Location	15q25.1
Locus type	gene with protein product
Status	Approved
Aliases	KIP2
Ensembl gene	ENSG00000136425
Ensembl biotype	protein_coding
OMIM	605564
Entrez	10518

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 3 nonsense_mediated_decay

ENST00000258930, ENST00000539011, ENST00000557818, ENST00000557846, ENST00000557917, ENST00000559054, ENST00000559645, ENST00000560618, ENST00000561190, ENST00000643268, ENST00000935334, ENST00000958911

RefSeq mRNA: 4 — MANE Select: NM_006383 NM_001271888, NM_001271889, NM_001301224, NM_006383

CCDS: CCDS10296, CCDS61722, CCDS61723

Canonical transcript exons

ENST00000258930 — 6 exons

Exon	Start	End
ENSE00001284128	78104606	78105332
ENSE00001322417	78131165	78131445
ENSE00003476144	78105739	78105934
ENSE00003629140	78109235	78109382
ENSE00003655126	78111165	78111276
ENSE00003682818	78123705	78123739

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 94.26.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.5103 / max 128.4859, expressed in 1297 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151098	4.0528	1130
151096	1.9260	653
151100	0.5323	264
151099	0.4591	259
151097	0.4285	240
207600	0.1116	40

Top tissues by expression

294 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right atrium auricular region	UBERON:0006631	94.26	gold quality
cardiac atrium	UBERON:0002081	93.83	gold quality
apex of heart	UBERON:0002098	93.67	gold quality
sperm	CL:0000019	93.34	gold quality
cervix squamous epithelium	UBERON:0006922	92.49	silver quality
ganglionic eminence	UBERON:0004023	91.94	gold quality
male germ cell	CL:0000015	91.67	gold quality
jejunal mucosa	UBERON:0000399	91.29	gold quality
embryo	UBERON:0000922	90.43	gold quality
ventricular zone	UBERON:0003053	89.87	gold quality
left testis	UBERON:0004533	88.95	gold quality
right testis	UBERON:0004534	88.78	gold quality
duodenum	UBERON:0002114	87.88	gold quality
testis	UBERON:0000473	87.77	gold quality
cortical plate	UBERON:0005343	87.40	gold quality
cardiac muscle of right atrium	UBERON:0003379	86.90	gold quality
hair follicle	UBERON:0002073	86.62	gold quality
cranial nerve II	UBERON:0000941	85.84	gold quality
jejunum	UBERON:0002115	85.70	gold quality
myocardium	UBERON:0002349	85.49	gold quality
dorsal root ganglion	UBERON:0000044	85.47	gold quality
heart	UBERON:0000948	85.45	gold quality
cingulate cortex	UBERON:0003027	84.88	gold quality
vena cava	UBERON:0004087	84.83	gold quality
anterior cingulate cortex	UBERON:0009835	84.76	gold quality
thymus	UBERON:0002370	84.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.54	gold quality
stromal cell of endometrium	CL:0002255	84.49	gold quality
right adrenal gland cortex	UBERON:0035827	84.33	gold quality
amygdala	UBERON:0001876	84.17	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4

miRNA regulators (miRDB)

39 targeting CIB2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-7109-5P	99.18	66.13	1057
HSA-MIR-153-3P	98.96	72.51	1644
HSA-MIR-6771-3P	98.20	66.53	971
HSA-MIR-660-3P	98.14	66.04	1434
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-6757-5P	98.08	65.50	724

Literature-anchored findings (GeneRIF, showing 13)

• CIB2, as binding partners for the integrin alphaIIb subunit, which suggests that they are potentially involved in regulating integrin alphaIIb subunit activation. (PMID:22779914)
• Consistent with molecular modeling predictions of calcium binding, CIB2 significantly decreased the ATP-induced calcium responses in heterologous cells, whereas mutations in deafness DFNB48 altered CIB2 effects on calcium responses (PMID:23023331)
• Data indicate that that CIB2 localizes to stereocilia and interacts with the USH proteins myosin VIIa and whirlin, suggesting CIB2 is a Ca2+-buffering protein essential for calcium homeostasis in the mechanosensory stereocilia of inner ear hair cells. (PMID:24022220)
• Novel homozygous missense variant c.196C>T and compound heterozygous variants, c.[97C>T];[196C>T], were associated with nonsyndromic deafness. (PMID:26173970)
• We identified a novel variant (rs7164338) on chromosome 15q25.1 in the CIB2 associated with lower pulse wave velocity. (PMID:26378684)
• CIB2 (Calcium and Integrin Binding Protein 2) Mutation Associated with Non-Syndromic Hearing Loss in a Hispanic Family (PMID:26426422)
• this study identifies CIB1 and CIB2 as host helper factors for HIV-1 replication that are required for optimal receptor-mediated viral entry (PMID:27489023)
• High CIB2 expression is associated with ovarian Cancer. (PMID:28729416)
• results suggest that GJB2 and CIB2 are common cause of hearing loss in different Pakistani ethnicities (PMID:29086887)
• This report is the first to show that biallelic LOF variants in CIB2 cause ARNSHL and not USH. In the era of precision medicine, providing the correct diagnosis (NSHL vs USH) is essential for patient care as it impacts potential intervention and prevention options for patients (PMID:29112224)
• Oligomeric state, hydrodynamic properties and target recognition of human Calcium and Integrin Binding protein 2 (CIB2). (PMID:31636333)
• CIB2 and CIB3 are auxiliary subunits of the mechanotransduction channel of hair cells. (PMID:34089643)
• Calcium- and Integrin-Binding Protein 2 (CIB2) in Physiology and Disease: Bright and Dark Sides. (PMID:35408910)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	cib2	ENSDARG00000102820
mus_musculus	Cib2	ENSMUSG00000037493
rattus_norvegicus	Cib2	ENSRNOG00000079672
drosophila_melanogaster	CG32812	FBGN0025642
drosophila_melanogaster	Cib2	FBGN0034558
drosophila_melanogaster	elm	FBGN0037358
drosophila_melanogaster	CG14362	FBGN0038186
caenorhabditis_elegans	calm-1	WBGENE00009260
caenorhabditis_elegans		WBGENE00014109
caenorhabditis_elegans		WBGENE00019108

Paralogs (8): TESC (ENSG00000088992), CIB3 (ENSG00000141977), CIB4 (ENSG00000157884), CHP2 (ENSG00000166869), CIB1 (ENSG00000185043), CHP1 (ENSG00000187446), PPP3R2 (ENSG00000188386), PPP3R1 (ENSG00000221823)

Protein

Protein identifiers

Calcium and integrin-binding family member 2 — O75838 (reviewed: O75838)

Alternative names: Kinase-interacting protein 2

All UniProt accessions (8): A0A2R8Y4Y2, O75838, H0YKC8, H0YKX8, H0YLL7, H0YLX3, H0YML3, H0YND4

UniProt curated annotations — full annotation on UniProt →

Function. Calcium- and integrin-binding protein that plays a role in intracellular calcium homeostasis. Acts as an auxiliary subunit of the sensory mechanoelectrical transduction (MET) channel in hair cells. Essential for mechanoelectrical transduction (MET) currents in auditory hair cells and thereby required for hearing. Regulates the function of hair cell mechanotransduction by controlling the distribution of transmembrane channel-like proteins TMC1 and TMC2, and by regulating the function of the MET channels in hair cells. Required for the maintenance of auditory hair cell stereocilia bundle morphology and function and for hair-cell survival in the cochlea. Critical for proper photoreceptor cell maintenance and function. Plays a role in intracellular calcium homeostasis by decreasing ATP-induced calcium release.

Subunit / interactions. Monomer. Homodimer. Interacts with WHRN and MYO7A. Interacts with ITGA2B (via C-terminus cytoplasmic tail region); the interactions are stabilized/increased in a calcium and magnesium-dependent manner. Interacts with ITGA7 (via C-terminus cytoplasmic tail region); the interactions are stabilized/increased in a calcium and magnesium-dependent manner. Interacts with TMC1. Interacts with TMC2.

Subcellular location. Cytoplasm. Cell projection. Stereocilium. Photoreceptor inner segment. Cilium. Photoreceptor outer segment. Cell membrane. Sarcolemma.

Tissue specificity. Widely expressed.

Disease relevance. Deafness, autosomal recessive, 48 (DFNB48) [MIM:609439] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. DFNB48 patients have prelingual onset of severe to profound sensorineural hearing loss affecting all frequencies. The disease is caused by variants affecting the gene represented in this entry. Usher syndrome 1J (USH1J) [MIM:614869] USH is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. The binding of either calcium or magnesium significantly increases the structural stability of the protein in comparison to apo-CIB (calcium- and magnesium-free form).

Isoforms (4)

UniProt ID	Names	Canonical?
O75838-1	1	yes
O75838-2	2
O75838-3	3
O75838-4	4

RefSeq proteins (4): NP_001258817, NP_001258818, NP_001288153, NP_006374* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR051433	CIBP	Family

Pfam: PF13499

UniProt features (42 total): helix 10, binding site 9, sequence variant 9, strand 5, domain 3, splice variant 3, turn 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8XOQ	X-RAY DIFFRACTION	2.41

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75838-F1	88.71	0.68

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (9): 161; 163; 168; 116; 118; 120; 127; 157; 159

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 175 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, KYNG_DNA_DAMAGE_DN, CTATGCA_MIR153, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_ATP, MODULE_205, GOBP_PHOTORECEPTOR_CELL_MAINTENANCE, KYNG_DNA_DAMAGE_BY_GAMMA_RADIATION, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_ATP, LIAO_METASTASIS, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND

GO Biological Process (4): positive regulation of cytosolic calcium ion concentration (GO:0007204), photoreceptor cell maintenance (GO:0045494), calcium ion homeostasis (GO:0055074), cellular response to ATP (GO:0071318)

GO Molecular Function (7): magnesium ion binding (GO:0000287), integrin binding (GO:0005178), calcium ion binding (GO:0005509), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), protein-containing complex binding (GO:0044877), metal ion binding (GO:0046872)

GO Cellular Component (14): photoreceptor outer segment (GO:0001750), photoreceptor inner segment (GO:0001917), cytoplasm (GO:0005737), muscle tendon junction (GO:0005927), neuromuscular junction (GO:0031594), stereocilium (GO:0032420), cuticular plate (GO:0032437), sarcolemma (GO:0042383), cell periphery (GO:0071944), blood microparticle (GO:0072562), plasma membrane (GO:0005886), cilium (GO:0005929), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Sensory processing of sound	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
metal ion binding	2
binding	2
regulation of biological quality	1
retina homeostasis	1
multicellular organismal process	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
response to ATP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
signaling receptor binding	1
protein-containing complex binding	1
cell adhesion molecule binding	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
photoreceptor cell cilium	1
intracellular anatomical structure	1
cell-substrate junction	1
synapse	1
stereocilium bundle	1
neuron projection	1
actin-based cell projection	1
cortical actin cytoskeleton	1
plasma membrane	1
extracellular region	1
membrane	1
cell periphery	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

2040 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CIB2	LHFPL5	Q8TAF8	936
CIB2	TMC1	Q8TDI8	906
CIB2	TMC2	Q8TDI7	905
CIB2	PCDH15	Q96QU1	879
CIB2	WHRN	Q9P202	861
CIB2	MYO7A	P78427	857
CIB2	CDH23	Q9H251	841
CIB2	USH1G	Q495M9	823
CIB2	E9PNW1	E9PNW1	812
CIB2	CLRN1	P58418	807
CIB2	PDZD7	Q9H5P4	768
CIB2	TMIE	Q8NEW7	752
CIB2	MYO15A	Q9UKN7	751
CIB2	ADGRV1	Q8WXG9	741
CIB2	USH2A	O75445	722

IntAct

124 interactions, top by confidence:

A	B	Type	Score
EMC2	EMC8	psi-mi:“MI:0914”(association)	0.940
CIB2	PARD3B	psi-mi:“MI:0407”(direct interaction)	0.590
CIB2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	GORASP1	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	GRIP2	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	MPP7	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	GORASP2	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
PARD3	CIB2	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	LNX1	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	RADIL	psi-mi:“MI:0407”(direct interaction)	0.440
HTRA1	CIB2	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	APBA1	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
PATJ	CIB2	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	CIB2	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	GIPC2	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	PCLO	psi-mi:“MI:0407”(direct interaction)	0.440
CIB2	PDZRN4	psi-mi:“MI:0407”(direct interaction)	0.440
DLG1	CIB2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (85): CIB2 (Affinity Capture-MS), CIB2 (Affinity Capture-RNA), CIB2 (Affinity Capture-MS), PLD2 (Affinity Capture-MS), RNF19B (Affinity Capture-MS), SLC27A6 (Affinity Capture-MS), B3GNT2 (Affinity Capture-MS), RAD21 (Affinity Capture-MS), FAM208A (Affinity Capture-MS), PARD3B (Affinity Capture-MS), TSEN2 (Affinity Capture-MS), SETX (Affinity Capture-MS), PDZD8 (Affinity Capture-MS), EPHA4 (Affinity Capture-MS), ATP13A2 (Affinity Capture-MS)

ESM2 similar proteins: C7A276, O73763, O75838, O81445, P06814, P06815, P28782, P29104, P35332, P36608, P43367, P62166, P62167, P62168, P62760, P62761, P62762, P62763, P62764, P80363, Q06389, Q09711, Q0P523, Q0VFG3, Q16981, Q2V8Y7, Q3YLA4, Q4R5F7, Q54MF3, Q568Z7, Q5R6S5, Q5RC90, Q5RD22, Q5XJX1, Q63ZJ3, Q6PC72, Q75K28, Q75KU4, Q874T7, Q8BGZ1

Diamond homologs: A0PJX0, B1A8Z2, C7A276, C7A278, O75838, Q0IQB6, Q0IUU4, Q0P523, Q17QE5, Q3KQ77, Q568Z7, Q6PC72, Q96Q77, Q99828, Q9D9N5, Q9R010, Q9W2Q5, Q9Y6T7, Q9Z0F4, Q9Z309, G5EDN6, P28470, P63098, P63099, P63100, Q2TBI5, Q3HRN8, Q3HRN9, Q63810, Q63811, Q6CGE6, Q7XC27, Q96LZ3, Q9LTB8, O81223, O81445, P06707, P06708, P0CM54, P0CM55

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
magnesium(2+)	“up-regulates activity”	CIB2	“chemical activation”
calcium(2+)	“up-regulates activity”	CIB2	“chemical activation”
CIB2	“up-regulates activity”	“a7/b1 integrin”	binding
CIB2	“up-regulates activity”	“AIIB/b3 integrin”	binding
CIB2	“down-regulates activity”	mTORC1	binding
CIB2	“up-regulates activity”	TMC1	binding
CIB2	“up-regulates activity”	TMC2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	52.9×	2e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	50.4×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	50.4×	2e-06
Long-term potentiation	5	44.1×	3e-06
Assembly and cell surface presentation of NMDA receptors	9	42.3×	5e-11
Neurexins and neuroligins	10	36.5×	2e-11
Protein-protein interactions at synapses	6	29.5×	2e-06
RHOA GTPase cycle	5	6.9×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	79.9×	2e-16
protein localization to synapse	6	57.5×	9e-08
receptor clustering	7	54.6×	9e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	7	43.4×	4e-08
protein-containing complex assembly	9	12.8×	2e-06
cell-cell adhesion	10	12.7×	5e-07
chemical synaptic transmission	7	6.8×	2e-03
nervous system development	8	4.6×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

250 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	6
Uncertain significance	87
Likely benign	99
Benign	23

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1058577	NM_006383.4(CIB2):c.542+1G>A	Pathogenic
1367570	NM_006383.4(CIB2):c.310C>T (p.Arg104Ter)	Pathogenic
1420092	NM_006383.4(CIB2):c.40_47del (p.Asp14fs)	Pathogenic
1446454	NM_006383.4(CIB2):c.301_311del (p.Ser101fs)	Pathogenic
1454880	NM_006383.4(CIB2):c.309_310del (p.Glu105fs)	Pathogenic
1455258	NM_006383.4(CIB2):c.385G>T (p.Glu129Ter)	Pathogenic
2444489	NM_006383.4(CIB2):c.476_479del (p.Asp159fs)	Pathogenic
3601861	NM_006383.4(CIB2):c.175del (p.Ile59fs)	Pathogenic
3601868	NM_006383.4(CIB2):c.286del (p.Ser96fs)	Pathogenic
3601879	NM_006383.4(CIB2):c.375_381del (p.Lys125fs)	Pathogenic
3601900	NM_006383.4(CIB2):c.384_385insT (p.Glu129Ter)	Pathogenic
3601911	NM_006383.4(CIB2):c.530del (p.Pro177fs)	Pathogenic
3601920	NM_006383.4(CIB2):c.531del (p.Asp178fs)	Pathogenic
39687	NM_006383.4(CIB2):c.368T>C (p.Ile123Thr)	Pathogenic
39688	NM_006383.4(CIB2):c.192G>C (p.Glu64Asp)	Pathogenic
4809535	NM_006383.4(CIB2):c.280_281del (p.Met94fs)	Pathogenic
816953	NM_006383.4(CIB2):c.97C>T (p.Arg33Ter)	Pathogenic
2430854	NM_006383.4(CIB2):c.347-2A>C	Likely pathogenic
2501662	NM_006383.4(CIB2):c.199-1G>A	Likely pathogenic
2635022	NM_006383.4(CIB2):c.199-125G>A	Likely pathogenic
3601889	NM_006383.4(CIB2):c.383_384insTA (p.Glu129fs)	Likely pathogenic
39685	NM_006383.4(CIB2):c.272T>C (p.Phe91Ser)	Likely pathogenic
4796692	NM_006383.4(CIB2):c.34C>T (p.Gln12Ter)	Likely pathogenic

SpliceAI

913 predictions. Top by Δscore:

Variant	Effect	Δscore
15:78105766:ATGT:A	donor_gain	1.0000
15:78105769:T:TA	donor_gain	1.0000
15:78105795:G:A	donor_gain	1.0000
15:78105817:T:TA	donor_gain	1.0000
15:78105930:GAAGT:G	acceptor_gain	1.0000
15:78105931:AAGT:A	acceptor_gain	1.0000
15:78105932:AGT:A	acceptor_gain	1.0000
15:78105933:GT:G	acceptor_gain	1.0000
15:78105933:GTCT:G	acceptor_loss	1.0000
15:78105934:TCTGT:T	acceptor_loss	1.0000
15:78105935:C:CC	acceptor_gain	1.0000
15:78105935:CT:C	acceptor_loss	1.0000
15:78109378:TTCTC:T	acceptor_gain	1.0000
15:78109380:CTC:C	acceptor_gain	1.0000
15:78109382:CCT:C	acceptor_loss	1.0000
15:78109383:C:CC	acceptor_gain	1.0000
15:78109383:CT:C	acceptor_loss	1.0000
15:78111159:ACAT:A	donor_loss	1.0000
15:78111160:CATA:C	donor_loss	1.0000
15:78111162:TACCC:T	donor_loss	1.0000
15:78111163:A:T	donor_loss	1.0000
15:78111163:AC:A	donor_gain	1.0000
15:78111164:CC:C	donor_gain	1.0000
15:78111278:T:C	acceptor_gain	1.0000
15:78123703:A:AC	donor_gain	1.0000
15:78123703:AC:A	donor_loss	1.0000
15:78123704:C:CA	donor_gain	1.0000
15:78105333:C:CC	acceptor_gain	0.9900
15:78105733:CAGCA:C	donor_loss	0.9900
15:78105734:AGCAC:A	donor_loss	0.9900

AlphaMissense

1266 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:78105326:G:C	F183L	1.000
15:78105326:G:T	F183L	1.000
15:78105328:A:G	F183L	1.000
15:78105815:C:G	A156P	1.000
15:78109249:G:T	A111D	1.000
15:78109260:C:A	K107N	1.000
15:78109260:C:G	K107N	1.000
15:78111169:A:G	L65P	1.000
15:78105744:G:C	F179L	0.999
15:78105744:G:T	F179L	0.999
15:78105745:A:G	F179S	0.999
15:78105746:A:G	F179L	0.999
15:78105755:C:G	A176P	0.999
15:78105774:G:C	F169L	0.999
15:78105774:G:T	F169L	0.999
15:78105775:A:G	F169S	0.999
15:78105776:A:G	F169L	0.999
15:78105877:A:G	L135P	0.999
15:78105886:A:G	L132P	0.999
15:78105898:A:G	L128P	0.999
15:78105901:T:G	D127A	0.999
15:78105902:C:G	D127H	0.999
15:78105913:A:T	I123N	0.999
15:78109235:C:G	D116H	0.999
15:78109245:G:C	F112L	0.999
15:78109245:G:T	F112L	0.999
15:78109246:A:G	F112S	0.999
15:78109247:A:G	F112L	0.999
15:78109247:A:T	F112I	0.999
15:78109250:C:G	A111P	0.999

dbSNP variants (sampled 300 via entrez): RS1000036038 (15:78107452 C>T), RS1000040050 (15:78125116 T>C), RS1000116485 (15:78111948 G>A), RS1000190547 (15:78130823 G>A), RS1000507446 (15:78118784 C>T), RS1000560892 (15:78107756 T>C), RS1000588481 (15:78126144 C>A,G,T), RS1000923041 (15:78131858 GAGA>G), RS1000945873 (15:78123362 C>T), RS1001156753 (15:78130045 C>T), RS1001237110 (15:78120724 C>G), RS1001286783 (15:78115218 C>G), RS1001313493 (15:78115426 A>AT), RS1001403769 (15:78124398 G>A), RS1001457311 (15:78121718 G>C)

Disease associations

OMIM: gene MIM:605564 | disease phenotypes: MIM:609439, MIM:614869, MIM:220290, MIM:607197, MIM:276900

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
Usher syndrome type 1J	Definitive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 48	Strong	Autosomal recessive
Usher syndrome type 1	Supportive	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Usher syndrome type 1	Refuted	AR
nonsyndromic genetic hearing loss	Definitive	AR

Mondo (8): autosomal recessive nonsyndromic hearing loss 48 (MONDO:0012273), hearing loss disorder (MONDO:0005365), inherited retinal dystrophy (MONDO:0019118), hearing loss, autosomal recessive (MONDO:0019588), Usher syndrome type 1 (MONDO:0010168), Usher syndrome (MONDO:0019501), nonsyndromic genetic hearing loss (MONDO:0019497), (MONDO:0013935)

Orphanet (6): Usher syndrome type 1 (Orphanet:231169), Usher syndrome (Orphanet:886), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare genetic deafness (Orphanet:96210)

HPO phenotypes

18 total (19 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000375	Abnormal cochlea morphology
HP:0000407	Sensorineural hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000572	Visual loss
HP:0000575	Scotoma
HP:0000662	Nyctalopia
HP:0000716	Depression
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0001270	Motor delay
HP:0001751	Abnormal vestibular function
HP:0002141	Gait imbalance
HP:0007663	Reduced visual acuity
HP:0007994	Peripheral visual field loss
HP:0011476	Profound sensorineural hearing impairment
HP:0000556	Retinal dystrophy

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003476_6	Eyebrow thickness	1.000000e-06

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D058499	Retinal Dystrophies	C11.768.585.658
D052245	Usher Syndromes	C09.218.458.341.186.500.500; C09.218.458.341.887.886; C10.597.751.418.341.186.500.500; C10.597.751.418.341.887.886; C10.597.751.941.162.625.500; C11.768.585.658.500.813; C11.966.075.375.500; C16.131.077.299.500; C16.320.290.684.500; C23.888.592.763.393.341.887.886
C564609	Deafness, Autosomal Recessive (supp.)
C563720	Deafness, Autosomal Recessive 48 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
Benzo(a)pyrene	increases expression, increases methylation	2
fluorene-9-bisphenol	decreases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	decreases expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
jinfukang	increases expression	1
Arsenic	increases expression	1
Carbamazepine	affects expression	1
Methapyrilene	increases methylation	1
Thimerosal	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Vitamin E	increases expression	1
Acrylamide	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2UD	Abcam HEK293T CIB2 KO	Transformed cell line	Female

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound