CAPN1

protein-coding

calpain 1, the group of Calpains|EF-hand domain containing

Gene summary

The calpains, calcium-activated neutral proteases, are nonlysosomal, intracellular cysteine proteases. The mammalian calpains include ubiquitous, stomach-specific, and muscle-specific proteins. The ubiquitous enzymes consist of heterodimers with distinct large, catalytic subunits associated with a common small, regulatory subunit. This gene encodes the large subunit of the ubiquitous enzyme, calpain 1. Several transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Nov 2010]

MANE transcript

NM_005186.4

Inheritance

ClinVar variants

P:49U:173B:80

Top phenotype

Spastic paraplegia 76, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.5

Max pathogenic AF

—

Genomic locus

chr11:65,180,566-65,212,006

External References & Databases

Ensembl (ENSG00000014216)

Transcript & Mutation Effects

hg38 • Region Span ~31.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive spastic paraplegia type 76STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014827

Submitter: Ambry Genetics

autosomal recessive spastic paraplegia type 76STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014827

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Spastic paraplegia 76, autosomal recessiveAR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 27153400

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAPN1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 249

Inborn genetic diseasesTotal: 99

Autosomal recessive spastic paraplegia type 76Total: 40

not specifiedTotal: 40

CAPN1-related disorderTotal: 13

Hereditary spastic paraplegia 11Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005186.4. 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			2 clinvar	66 clinvar	3 clinvar	71
missense	4 clinvar	1 clinvar	159 clinvar	10 clinvar	1 clinvar	175
nonsense	12 clinvar	8 clinvar	1 clinvar			21
start loss						0
frameshift	10 clinvar	2 clinvar				12
splice donor/acceptor (+/-2bp)	6 clinvar	6 clinvar	11 clinvar			23
Total	32	17	173	76	4	302

Highest pathogenic variant AF is 0.000105541556

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005186.4	RefSeq	NP_005177.2	21	MANE Select
ENST00000279247.11	Ensembl	ENSP00000279247.7	21	MANE Select
NM_001198868.2	RefSeq	NP_001185797.1	21	Standard
NM_001198869.2	RefSeq	NP_001185798.1	21	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
capn1a	Danio rerio	Structure: neuron Quality: disorganized abnormal

Gene / Model

Organism

Observed Phenotype

capn1a

Danio rerio

Structure: neuron

Quality: disorganized

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Protein processing in endoplasmic reticulum - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Necroptosis - Homo sapiens (human)
Apoptosis - Homo sapiens (human)
Cellular senescence - Homo sapiens (human)

Biological Process

proteolysis
positive regulation of cell population proliferation
regulation of macroautophagy
receptor catabolic process
neutrophil degranulation

Molecular Function

endopeptidase activity
calcium-dependent cysteine-type endopeptidase activity
calcium ion binding
protein binding

Cellular Component

extracellular region
cytoplasm
mitochondrion
lysosome
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000527323
Coding exons: 21
Length: 31441
Individuals with no LoFs: 124649
Homozygous LoFs: 0
Heterozygous LoFs: 71
Defined: 124720
p: 0.000285

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.68	369	472	0.782	0.0000315	4636
Missense (PolyPhen)		135	194.01	0.69583		1899
Synonymous	2.48	149	193	0.773	0.0000134	1354
Loss of Function	3.16	23	46.1	0.499	0.00000257	470

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.0011	notable
Latino/Admixed American	0.00044	0.00043	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00021	0.00021	rare
South Asian	0.00023	0.00023	rare
Other	0.00017	0.00017	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. {ECO:0000269|PubMed:21531719, ECO:0000269|PubMed:2400579}.;
Disease: DISEASE: Spastic paraplegia 76, autosomal recessive (SPG76) [MIM:616907]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. {ECO:0000269|PubMed:27153400}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.340

Intolerance Scores

LoFtool: 0.500
RVIS EVS: -0.33
RVIS percentile EVS: 30.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.624

Gene Damage Prediction

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