CAPN3

calpain 3, the group of Calpains|EF-hand domain containing

Basic information

Region (hg38): 15:42359498-42412949

Previous symbols: [ "LGMD2", "LGMD2A" ]

Links

ENSG00000092529 ∙ NCBI:825 ∙ OMIM:114240 ∙ HGNC:1480 ∙ Uniprot:P20807 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal recessive limb-girdle muscular dystrophy type 2A (Definitive), mode of inheritance: AR
• autosomal recessive limb-girdle muscular dystrophy type 2A (Supportive), mode of inheritance: AR
• muscular dystrophy, limb-girdle, autosomal dominant 4 (Moderate), mode of inheritance: AD
• autosomal recessive limb-girdle muscular dystrophy type 2A (Strong), mode of inheritance: AR
• muscular dystrophy, limb-girdle, autosomal dominant 4 (Strong), mode of inheritance: AD
• muscular dystrophy, limb-girdle, autosomal dominant (Limited), mode of inheritance: AD
• autosomal recessive limb-girdle muscular dystrophy (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Muscular dystrophy, limb-girdle, autosomal dominant 4; Muscular dystrophy, limb-girdle, autosomal recessive, 1	AD/AR	General	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	Musculoskeletal	7720071; 10069710; 10330340; 15694138; 16607617; 16971480; 18854869; 21204801; 22378277; 22622166; 22926650; 27259757; 28881388

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CAPN3 gene.

• Autosomal recessive limb-girdle muscular dystrophy type 2A (166 variants)
• not provided (75 variants)
• Muscular dystrophy, limb-girdle, autosomal dominant 4 (66 variants)
• Autosomal recessive limb-girdle muscular dystrophy (10 variants)
• Abnormality of the musculature (10 variants)
• Autosomal recessive limb-girdle muscular dystrophy type 2A;Muscular dystrophy, limb-girdle, autosomal dominant 4 (8 variants)
• CAPN3-related disorder (4 variants)
• Shoulder girdle muscle weakness;Calf muscle hypertrophy (1 variants)
• Myopathy;Muscle weakness;Absent Achilles reflex (1 variants)
• Shoulder girdle muscle weakness;EMG: myopathic abnormalities (1 variants)
• See cases (1 variants)
• Muscular dystrophy (1 variants)
• Limb-girdle muscular dystrophy, recessive (1 variants)
• Elbow flexion contracture;Cardiac arrhythmia;Muscular dystrophy;Lower-limb joint contracture;Muscle weakness (1 variants)
• Myositis, eosinophilic (1 variants)
• Muscular dystrophy;Shoulder girdle muscle weakness;Limb-girdle muscle weakness (1 variants)
• Congenital muscular dystrophy (1 variants)
• 8 conditions (1 variants)
• Qualitative or quantitative defects of calpain (1 variants)
• Muscular dystrophy;Cardiac arrhythmia;Muscle weakness;Lower-limb joint contracture;Elbow flexion contracture (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CAPN3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	1	1	10	286		298
missense	21	67	433	9		530
nonsense	43	32				75
start loss	3	1	4			8
frameshift	96	56	5			157
inframe indel	3	3	16			22
splice donor/acceptor (+/-2bp)	28	47				75
splice region	2	7	42	72	1	124
non coding	4	3	35	260	67	369
Total	199	210	503	555	67

Highest pathogenic variant AF is 0.000197

Variants in CAPN3

This is a list of pathogenic ClinVar variants found in the CAPN3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-42359506-C-G		Limb-girdle muscular dystrophy, recessive • Autosomal recessive limb-girdle muscular dystrophy type 2A	Uncertain significance (Jan 12, 2018)
15-42359675-G-T		Limb-girdle muscular dystrophy, recessive • Autosomal recessive limb-girdle muscular dystrophy type 2A • Muscular dystrophy, limb-girdle, autosomal dominant 4;Autosomal recessive limb-girdle muscular dystrophy type 2A	Uncertain significance (Jul 24, 2021)
15-42359702-G-C		Limb-girdle muscular dystrophy, recessive • Autosomal recessive limb-girdle muscular dystrophy type 2A	Conflicting classifications of pathogenicity (May 18, 2021)
15-42359710-A-T		Autosomal recessive limb-girdle muscular dystrophy type 2A	Uncertain significance (Jan 12, 2018)
15-42359781-G-C		not specified	Likely benign (Jun 06, 2017)
15-42359806-A-G		Autosomal recessive limb-girdle muscular dystrophy type 2A	Pathogenic (Oct 06, 2023)
15-42359806-AT-A		Autosomal recessive limb-girdle muscular dystrophy type 2A	Pathogenic (Oct 25, 2022)
15-42359807-T-C		Autosomal recessive limb-girdle muscular dystrophy type 2A	Likely pathogenic (Feb 13, 2018)
15-42359808-G-T		Autosomal recessive limb-girdle muscular dystrophy type 2A	Pathogenic (Oct 03, 2022)
15-42359810-C-G		Autosomal recessive limb-girdle muscular dystrophy type 2A	Uncertain significance (Feb 08, 2022)
15-42359811-G-A		Autosomal recessive limb-girdle muscular dystrophy type 2A	Likely benign (Jan 04, 2023)
15-42359811-G-T		Autosomal recessive limb-girdle muscular dystrophy type 2A	Likely benign (Jul 24, 2023)
15-42359812-A-G		Autosomal recessive limb-girdle muscular dystrophy type 2A • Muscular dystrophy, limb-girdle, autosomal dominant 4;Autosomal recessive limb-girdle muscular dystrophy type 2A	Uncertain significance (Jun 16, 2022)
15-42359814-C-T		Autosomal recessive limb-girdle muscular dystrophy type 2A	Likely benign (Jan 27, 2024)
15-42359815-G-A		Autosomal recessive limb-girdle muscular dystrophy type 2A • Autosomal recessive limb-girdle muscular dystrophy type 2A;Muscular dystrophy, limb-girdle, autosomal dominant 4 • not specified	Uncertain significance (Aug 07, 2024)
15-42359817-C-T		Autosomal recessive limb-girdle muscular dystrophy type 2A	Likely benign (Sep 08, 2023)
15-42359818-A-G		Autosomal recessive limb-girdle muscular dystrophy type 2A	Uncertain significance (Feb 02, 2022)
15-42359823-C-T		Autosomal recessive limb-girdle muscular dystrophy type 2A	Likely benign (Jan 22, 2024)
15-42359824-G-A		Autosomal recessive limb-girdle muscular dystrophy type 2A	Uncertain significance (Nov 08, 2023)
15-42359824-G-C			Uncertain significance (Jan 31, 2018)
15-42359829-T-C		Autosomal recessive limb-girdle muscular dystrophy type 2A	Likely benign (Dec 02, 2023)
15-42359830-G-C		Autosomal recessive limb-girdle muscular dystrophy type 2A	Uncertain significance (Jul 08, 2023)
15-42359844-A-G		Autosomal recessive limb-girdle muscular dystrophy type 2A	Likely benign (Jan 26, 2023)
15-42359846-C-A		Autosomal recessive limb-girdle muscular dystrophy type 2A • Inborn genetic diseases	Uncertain significance (Apr 19, 2024)
15-42359846-C-T		Autosomal recessive limb-girdle muscular dystrophy type 2A	Uncertain significance (Jun 12, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CAPN3	protein_coding	protein_coding	ENST00000397163	24	64216

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.59e-19	0.389	125568	0	180	125748	0.000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.0330	469	467	1.00	0.0000301	5494
Missense in Polyphen		185	202.29	0.91451		2331
Synonymous	-1.63	207	179	1.15	0.0000128	1472
Loss of Function	1.75	36	49.2	0.731	0.00000256	564

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00139	0.00139
Ashkenazi Jewish	0.00	0.00
East Asian	0.000653	0.000653
Finnish	0.000371	0.000370
European (Non-Finnish)	0.000968	0.000923
Middle Eastern	0.000653	0.000653
South Asian	0.000490	0.000490
Other	0.000654	0.000652

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Calcium-regulated non-lysosomal thiol-protease.
• Pathway: Integrin-mediated Cell Adhesion;Extracellular matrix organization;Degradation of the extracellular matrix (Consensus)

Recessive Scores

• pRec: 0.108

Intolerance Scores

• loftool: 0.0198
• rvis_EVS: -0.7
• rvis_percentile_EVS: 14.81

Haploinsufficiency Scores

• pHI: 0.790
• hipred: Y
• hipred_score: 0.706
• ghis: 0.511

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.864

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Capn3
• Phenotype: growth/size/body region phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); normal phenotype; reproductive system phenotype; muscle phenotype; homeostasis/metabolism phenotype

Gene ontology

• Biological process: proteolysis;apoptotic process;muscle organ development;positive regulation of satellite cell activation involved in skeletal muscle regeneration;response to muscle activity;protein catabolic process;myofibril assembly;protein destabilization;negative regulation of protein sumoylation;negative regulation of apoptotic process;regulation of I-kappaB kinase/NF-kappaB signaling;sarcomere organization;regulation of myoblast differentiation;positive regulation of proteolysis;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;muscle cell cellular homeostasis;regulation of catalytic activity;positive regulation of NF-kappaB transcription factor activity;positive regulation of release of sequestered calcium ion into cytosol;response to calcium ion;muscle structure development;protein-containing complex assembly;G1 to G0 transition involved in cell differentiation;cellular response to calcium ion;cellular response to salt stress;protein localization to membrane;self proteolysis;calcium-dependent self proteolysis
• Cellular component: nucleus;cytoplasm;cytosol;plasma membrane;myofibril;Z disc;T-tubule;protein-containing complex
• Molecular function: catalytic activity;calcium-dependent cysteine-type endopeptidase activity;calcium ion binding;protein binding;peptidase activity;cysteine-type peptidase activity;structural constituent of muscle;sodium ion binding;titin binding;protein-containing complex scaffold activity;ligase regulator activity