CAPN10

protein-coding

calpain 10, the group of Calpains

Gene summary

Calpains represent a ubiquitous, well-conserved family of calcium-dependent cysteine proteases. The calpain proteins are heterodimers consisting of an invariant small subunit and variable large subunits. The large catalytic subunit has four domains: domain I, the N-terminal regulatory domain that is processed upon calpain activation; domain II, the protease domain; domain III, a linker domain of unknown function; and domain IV, the calmodulin-like calcium-binding domain. This gene encodes a large subunit. It is an atypical calpain in that it lacks the calmodulin-like calcium-binding domain and instead has a divergent C-terminal domain. It is similar in organization to calpains 5 and 6. This gene is associated with type 2 or non-insulin-dependent diabetes mellitus (NIDDM), and is located within the NIDDM1 region. Multiple alternative transcript variants have been described for this gene. [provided by RefSeq, Sep 2010]

MANE transcript

NM_023083.4

Inheritance

ClinVar variants

P:4U:142B:43

Top phenotype

Inborn genetic diseases

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr2:240,586,734-240,617,705

External References & Databases

Ensembl (ENSG00000142330)

Transcript & Mutation Effects

hg38 • Region Span ~31.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAPN10 variants in ClinVar

5 Conditions Cataloged

Inborn genetic diseasesTotal: 130

not providedTotal: 29

CAPN10-related disorderTotal: 16

not specifiedTotal: 13

Diabetes mellitus, noninsulin-dependent, 1Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_023083.4. 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			6 clinvar	21 clinvar	2 clinvar	29
missense			127 clinvar	14 clinvar	6 clinvar	147
nonsense		1 clinvar	1 clinvar			2
start loss						0
frameshift	2 clinvar		1 clinvar			3
splice donor/acceptor (+/-2bp)	1 clinvar		7 clinvar			8
Total	3	1	142	35	8	189

Highest pathogenic variant AF is 0.000008894922

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 65 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_023083.4	RefSeq	NP_075571.2	12	MANE Select
ENST00000391984.7	Ensembl	ENSP00000375844.2	12	MANE Select
NM_023085.4	RefSeq	NP_075573.3	10	Standard
ENST00000270361.15	Ensembl	ENSP00000270361.11	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Integrin-mediated Cell Adhesion
Extracellular matrix organization
Degradation of the extracellular matrix

Biological Process

proteolysis
cellular component disassembly involved in execution phase of apoptosis
actin cytoskeleton reorganization
positive regulation of insulin secretion
positive regulation of intracellular transport

Molecular Function

SNARE binding
calcium-dependent cysteine-type endopeptidase activity
cytoskeletal protein binding

Cellular Component

cytoplasm
mitochondrion
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000391984
Coding exons: 12
Length: 30990
Individuals with no LoFs: 125671
Homozygous LoFs: 0
Heterozygous LoFs: 76
Defined: 125747
p: 0.000302

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.17	357	425	0.841	0.0000282	4261
Missense (PolyPhen)		123	152.26	0.80784		1682
Synonymous	-0.697	207	195	1.06	0.0000137	1426
Loss of Function	1.56	24	33.8	0.710	0.00000163	334

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.00079	0.00079	rare
European (Non-Finnish)	0.00029	0.00027	rare
South Asian	0.00017	0.00016	rare
Other	0.00066	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Calcium-regulated non-lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction. May play a role in insulin-stimulated glucose uptake. {ECO:0000269|PubMed:17572128}.;

Recessive Scores

pRec: 0.211

Intolerance Scores

LoFtool: 0.111
RVIS EVS: -0.33
RVIS percentile EVS: 30.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.160

Gene Damage Prediction

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