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 (1623 variants)
• not_provided (640 variants)
• Muscular_dystrophy,_limb-girdle,_autosomal_dominant_4 (285 variants)
• not_specified (133 variants)
• Autosomal_recessive_limb-girdle_muscular_dystrophy (91 variants)
• Inborn_genetic_diseases (81 variants)
• CAPN3-related_disorder (34 variants)
• Limb-girdle_muscular_dystrophy,_recessive (26 variants)
• Abnormality_of_the_musculature (19 variants)
• See_cases (5 variants)
• Muscle_weakness (3 variants)
• Limb-girdle_muscular_dystrophy (3 variants)
• Paresthesia (2 variants)
• Absent_Achilles_reflex (2 variants)
• Absent_muscle_fiber_calpain-3 (2 variants)
• Cardiac_arrhythmia (2 variants)
• Elbow_flexion_contracture (2 variants)
• Lower-limb_joint_contracture (2 variants)
• Positive_Romberg_sign (2 variants)
• Progressive_spinal_muscular_atrophy (2 variants)
• Migraine (2 variants)
• Elevated_circulating_creatine_kinase_concentration (2 variants)
• Difficulty_walking (2 variants)
• EMG:_neuropathic_changes (2 variants)
• Muscular_dystrophy (2 variants)
• Myopathy (2 variants)
• EMG:_myopathic_abnormalities (1 variants)
• Qualitative_or_quantitative_defects_of_calpain (1 variants)
• Familial_idiopathic_inflammatory_myopathy (1 variants)
• Autosomal_recessive_limb-girdle_muscular_dystrophy_type_2B (1 variants)
• Limb-girdle_muscle_weakness (1 variants)
• Congenital_muscular_dystrophy (1 variants)
• Autosomal_recessive_disease (1 variants)
• Myositis,_eosinophilic (1 variants)
• Calf_muscle_hypertrophy (1 variants)
• Shoulder_girdle_muscle_weakness (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. These statistics are base on transcript: NM_000000070.3. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous	2	3	24	356	1	386
missense	39	127	542	15	2	725
nonsense	42	41	4			87
start loss	3	1				4
frameshift	114	58	12			184
splice donor/acceptor (+/-2bp)	41	51	3			95
Total	241	281	585	371	3

Highest pathogenic variant AF is 0.00310349

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