CABP2

protein-coding

calcium binding protein 2, the group of EF-hand domain containing

Gene summary

This gene belongs to a subfamily of calcium binding proteins that share similarity to calmodulin. Like calmodulin, these family members can likely stimulate calmodulin-dependent kinase II and the protein phosphatase calcineurin. Calcium binding proteins are an important component of calcium mediated cellular signal transduction. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2016]

Previous symbols:

DFNB93

MANE transcript

NM_016366.3

Inheritance

ClinVar variants

P:9U:73B:31

Top phenotype

Deafness, autosomal recessive 93

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr11:67,518,912-67,524,517

External References & Databases

Ensembl (ENSG00000167791)

Transcript & Mutation Effects

hg38 • Region Span ~5.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 93STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013963

Submitter: G2P

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

CABP2 was first reported in relation to autosomal recessive nonsyndromic hearing loss in humans as early as 2012 (Schrauwen et al., PMID: 22981119). At least 4 unique variants (splice-site, nonsense, and missense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 4 probands in 4 publications (PMID: 22981119, 26226137, 28183797, 31661684). Variants in this gene segregated with disease in at least 12 additional family members. This gene-disease association is supported by animal models, expression studies, and in vitro function studies. In summary, CABP2 is definitively associated with autosomal recessive nonsyndromic hearing loss.

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

autosomal recessive nonsyndromic hearing loss 93STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013963

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 93AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 22981119; 21542834

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CABP2 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 113

Inborn genetic diseasesTotal: 34

not specifiedTotal: 18

CABP2-related disorderTotal: 16

Autosomal recessive nonsyndromic hearing loss 93Total: 10

Monogenic hearing lossTotal: 3

Hearing loss, autosomal recessiveTotal: 2

Nonsyndromic genetic hearing lossTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016366.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	24 clinvar		25
missense	1 clinvar		69 clinvar	6 clinvar	1 clinvar	77
nonsense	1 clinvar		1 clinvar			2
start loss			1 clinvar			1
frameshift		3 clinvar				3
splice donor/acceptor (+/-2bp)		4 clinvar	1 clinvar			5
Total	2	7	73	30	1	113

Highest pathogenic variant AF is 0.0010015295

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016366.3	RefSeq	NP_057450.2	7	MANE Select
ENST00000294288.5	Ensembl	ENSP00000294288.4	7	MANE Select
NM_001318496.2	RefSeq	NP_001305425.1	7	Standard
ENST00000353903.9	Ensembl	ENSP00000312037.4	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

signal transduction
visual perception
sensory perception of sound

Molecular Function

calcium channel regulator activity
calcium ion binding

Cellular Component

Golgi apparatus
plasma membrane
perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000294288
Coding exons: 7
Length: 4517
Individuals with no LoFs: 125474
Homozygous LoFs: 0
Heterozygous LoFs: 273
Defined: 125747
p: 0.00109

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0294	152	153	0.993	0.0000111	1410
Missense (PolyPhen)		69	78.605	0.87781		669
Synonymous	-0.481	71	66.0	1.08	0.00000487	454
Loss of Function	1.64	6	12.2	0.492	6.99e-7	126

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00062	0.00062	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.0034	0.0034	notable
European (Non-Finnish)	0.0011	0.0011	notable
South Asian	0.0016	0.0016	notable
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for sound encoding at inner hair cells (IHCs) synapses, likely via inhibition of the inactivation of voltage- gated calcium channel of type 1.3 (Cav1.3) in the IHCs (PubMed:28183797). Required for the normal transfer of light signals through the retina (By similarity). {ECO:0000250|UniProtKB:Q9JLK4, ECO:0000269|PubMed:28183797}.;

Recessive Scores

pRec: 0.115

Intolerance Scores

LoFtool: 0.434
RVIS EVS: 0.28
RVIS percentile EVS: 71.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.678

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	High	High