CAPNS1

protein-coding

calpain small subunit 1, the group of EF-hand domain containing

Gene summary

This gene is a member of the calpain small subunit family. Calpains are calcium-dependent cysteine proteinases that are widely distributed in mammalian cells. Calpains operate as heterodimers, comprising a specific large catalytic subunit (calpain 1 subunit in Calpain I, and calpain 2 subunit in Calpain II), and a common small regulatory subunit encoded by this gene. This encoded protein is essential for the stability and function of both calpain heterodimers, whose proteolytic activities influence various cellular functions including apoptosis, proliferation, migration, adhesion, and autophagy. Calpains have been implicated in neurodegenerative processes, such as myotonic dystrophy. A pseudogene of this gene has been defined on chromosome 1. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2014]

Previous symbols:

CAPN4

MANE transcript

NM_001749.4

Inheritance

ClinVar variants

P:3U:48B:3

Top phenotype

Pulmonary hypertension, primary, 6

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr19:36,139,953-36,150,353

External References & Databases

Ensembl (ENSG00000126247)

Transcript & Mutation Effects

hg38 • Region Span ~10.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

Clinical Genomic Database (CGD)

Pulmonary hypertension, primary, 6AR

Manifestation: Cardiovascular; Pulmonary

Intervention: Cardiovascular; Pulmonary

Rationale: The condition can involve severe, early-onset pulmonary hypertension, with related cardiovascular sequelae, and awareness may allow early identification and management

Refs: 38230350

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CAPNS1 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 34

not providedTotal: 3

Pulmonary hypertension, primary, 6Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001749.4. 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	3 clinvar		5
missense			35 clinvar			35
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	10 clinvar			13
Total	1	2	48	3	0	54

Highest pathogenic variant AF is 0.0000150330725

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 50 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001749.4	RefSeq	NP_001740.1	10	MANE Select
ENST00000246533.8	Ensembl	ENSP00000246533.2	10	MANE Select
NM_001003962.3	RefSeq	NP_001003962.1	10	Standard
NM_001302632.2	RefSeq	NP_001289561.1	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Apoptosis Modulation and Signaling
Integrin-mediated Cell Adhesion
Keratinization
Developmental Biology
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer,s disease models

Biological Process

proteolysis
positive regulation of cell population proliferation
regulation of macroautophagy
cornification

Molecular Function

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

Cellular Component

cytosol
plasma membrane
membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000246533
Coding exons: 10
Length: 10779
Individuals with no LoFs: 125699
Homozygous LoFs: 0
Heterozygous LoFs: 49
Defined: 125748
p: 0.000195

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.592	124	144	0.861	0.00000834	1745
Missense (PolyPhen)		37	54.776	0.67548		697
Synonymous	-1.13	62	51.6	1.20	0.00000280	504
Loss of Function	1.21	12	17.5	0.687	0.00000124	177

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.000059	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00030	0.00030	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulatory subunit of the calcium-regulated non- lysosomal thiol-protease which catalyzes limited proteolysis of substrates involved in cytoskeletal remodeling and signal transduction.;

Recessive Scores

pRec: 0.341

Intolerance Scores

LoFtool: 0.656
RVIS EVS: -0.27
RVIS percentile EVS: 33.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.828

Gene Damage Prediction

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