CACNA1S

calcium voltage-gated channel subunit alpha1 S, the group of Calcium voltage-gated channel alpha1 subunits

Basic information

Region (hg38): 1:201039512-201112451

Previous symbols: [ "HOKPP", "MHS5", "CACNL1A3" ]

Links

ENSG00000081248

∙ NCBI:779 ∙ OMIM:114208 ∙ HGNC:1397 ∙ Uniprot:Q13698 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

hypokalemic periodic paralysis, type 1 (Strong), mode of inheritance: AD
congenital myopathy (Strong), mode of inheritance: AD
congenital myopathy (Strong), mode of inheritance: AR
hypokalemic periodic paralysis, type 1 (Strong), mode of inheritance: AD
malignant hyperthermia, susceptibility to, 5 (Moderate), mode of inheritance: AD
hypokalemic periodic paralysis (Supportive), mode of inheritance: AD
congenital myopathy (Strong), mode of inheritance: Semidominant
hypokalemic periodic paralysis, type 1 (Strong), mode of inheritance: AD
malignant hyperthermia, susceptibility to, 5 (Strong), mode of inheritance: AD
congenital myopathy 18 (Strong), mode of inheritance: AR
congenital myopathy 18 (Strong), mode of inheritance: AD
malignant hyperthermia, susceptibility to, 5 (Moderate), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Malignant hyperthermia, susceptibility to, 5; Thyrotoxic period paralysis, susceptibility 1; Hypokalemic periodic paralysis, type 1	AD	Cardiovascular; Endocrine; Pharmacogenomic; Renal	In Malignant hyperthermia, early diagnosis, discontinuation of potent inhalation agents/succinylcholine, treatment of metabolic abnormalities, and administration of dantrolene sodium intravenously are essential to treat acute MH; In Thyrotoxic periodic paralysis, treatment of hyperthyroidism results in resolution of paralysis; In Hypokalemic periodic paralysis, paralytic crises can be treated with potassium; Dietary (eg, low sodium/carbohydrate) and medical (eg, potassium, acetazolamide) therapy can be effective; Cardiac surveillance can be beneficial	Cardiovascular; Endocrine; Musculoskeletal; Renal	1148686; 457125; 3855357; 3839536; 8004673; 7897626; 9199552; 11591859; 11353725; 15001631; 15534250; 18835861; 19118277; 20301512; 20301325; 22253645; 22094484; 22901280; 28012042; 31227654; 33060286; 34763287

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CACNA1S gene.

Malignant_hyperthermia,_susceptibility_to,_5 (2719 variants)
Hypokalemic_periodic_paralysis,_type_1 (2158 variants)
Thyrotoxic_periodic_paralysis,_susceptibility_to,_1 (631 variants)
not_provided (607 variants)
Congenital_myopathy_18 (581 variants)
Inborn_genetic_diseases (226 variants)
not_specified (168 variants)
CACNA1S-related_disorder (89 variants)
Malignant_hyperthermia_of_anesthesia (26 variants)
Hypokalemic_periodic_paralysis (19 variants)
Malignant_hyperthermia,_susceptibility_to,_1 (4 variants)
Long_QT_syndrome (4 variants)
Congenital_myopathy (4 variants)
Centronuclear_myopathy (3 variants)
enflurane_response_-_Toxicity (2 variants)
methoxyflurane_response_-_Toxicity (2 variants)
desflurane_response_-_Toxicity (2 variants)
halothane_response_-_Toxicity (2 variants)
Abnormality_of_the_musculature (2 variants)
sevoflurane_response_-_Toxicity (2 variants)
isoflurane_response_-_Toxicity (2 variants)
succinylcholine_response_-_Toxicity (2 variants)
Congenital_nuclear_cataract (1 variants)
Rhabdomyolysis (1 variants)
skeletal_contractures (1 variants)
Intellectual_disability (1 variants)
Malignant_hyperthermia,_susceptibility_to (1 variants)
Muscular_atrophy (1 variants)
Hereditary_liability_to_pressure_palsies (1 variants)
See_cases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CACNA1S gene is commonly pathogenic or not. These statistics are base on transcript: NM_000000069.3. 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	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			24 clinvar	661 clinvar	16 clinvar	701
missense	13 clinvar	15 clinvar	1223 clinvar	248 clinvar	14 clinvar	1513
nonsense	23 clinvar	19 clinvar	13 clinvar			55
start loss			1			1
frameshift	32 clinvar	19 clinvar	24 clinvar	1 clinvar		76
splice donor/acceptor (+/-2bp)		35 clinvar	16 clinvar			51
Total	68	88	1301	910	30

Highest pathogenic variant AF is 0.000078848585

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CACNA1S	protein_coding	protein_coding	ENST00000362061	44	73053

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
6.26e-12	1.00	125639	0	109	125748	0.000434

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.111	1075	1.06e+3	1.01	0.0000663	12336
Missense in Polyphen		460	460.25	0.99947		5288
Synonymous	-1.67	472	428	1.10	0.0000280	3641
Loss of Function	5.36	36	91.3	0.394	0.00000474	1064

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00203	0.00203
Ashkenazi Jewish	0.000298	0.000298
East Asian	0.000435	0.000435
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000335	0.000334
Middle Eastern	0.000435	0.000435
South Asian	0.000588	0.000588
Other	0.00	0.00

dbNSFP

Source: dbNSFP

Function: FUNCTION: Pore-forming, alpha-1S subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle. Calcium channels containing the alpha-1S subunit play an important role in excitation-contraction coupling in skeletal muscle via their interaction with RYR1, which triggers Ca(2+) release from the sarcplasmic reticulum and ultimately results in muscle contraction. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. {ECO:0000250|UniProtKB:P07293}.;
Disease: DISEASE: Periodic paralysis hypokalemic 1 (HOKPP1) [MIM:170400]: An autosomal dominant disorder manifested by episodic flaccid generalized muscle weakness associated with falls of serum potassium levels. {ECO:0000269|PubMed:17418573, ECO:0000269|PubMed:18162704, ECO:0000269|PubMed:19118277, ECO:0000269|PubMed:7987325, ECO:0000269|PubMed:8004673}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Malignant hyperthermia 5 (MHS5) [MIM:601887]: Autosomal dominant disorder that is potentially lethal in susceptible individuals on exposure to commonly used inhalational anesthetics and depolarizing muscle relaxants. {ECO:0000269|PubMed:9199552}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Thyrotoxic periodic paralysis 1 (TTPP1) [MIM:188580]: A sporadic muscular disorder characterized by episodic weakness and hypokalemia during a thyrotoxic state. It is clinically similar to hereditary hypokalemic periodic paralysis, except for the fact that hyperthyroidism is an absolute requirement for disease manifestation. The disease presents with recurrent episodes of acute muscular weakness of the four extremities that vary in severity from paresis to complete paralysis. Attacks are triggered by ingestion of a high carbohydrate load or strenuous physical activity followed by a period of rest. Thyrotoxic periodic paralysis can occur in association with any cause of hyperthyroidism, but is most commonly associated with Graves disease. {ECO:0000269|PubMed:15001631}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;
Pathway: Cortisol synthesis and secretion - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Oxytocin signaling pathway - Homo sapiens (human);Retrograde endocannabinoid signaling - Homo sapiens (human);GABAergic synapse - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Cardiac muscle contraction - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Renin secretion - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Celecoxib Pathway, Pharmacodynamics;Beta-agonist/Beta-blocker Pathway, Pharmacodynamics;Alzheimers Disease;Arrhythmogenic Right Ventricular Cardiomyopathy;MAPK Signaling Pathway;Calcium Regulation in the Cardiac Cell;Developmental Biology;GPCR Dopamine D1like receptor;Phase 0 - rapid depolarisation;Phase 2 - plateau phase;Cardiac conduction;Muscle contraction;NCAM signaling for neurite out-growth;NCAM1 interactions;Axon guidance (Consensus)

Intolerance Scores

loftool: 0.0300
rvis_EVS: -1.21
rvis_percentile_EVS: 5.71

Haploinsufficiency Scores

pHI: 0.226
hipred: Y
hipred_score: 0.544
ghis: 0.513

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: E
gene_indispensability_score: 0.833

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Cacna1s
Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); 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); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; skeleton phenotype; limbs/digits/tail phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); muscle phenotype; digestive/alimentary phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; cellular phenotype; homeostasis/metabolism phenotype; craniofacial phenotype;

Gene ontology

Biological process: calcium ion transport;muscle contraction;regulation of ion transmembrane transport;calcium ion import;calcium ion transmembrane transport;cellular response to caffeine
Cellular component: cytoplasm;plasma membrane;voltage-gated calcium channel complex;T-tubule;I band;L-type voltage-gated calcium channel complex
Molecular function: voltage-gated calcium channel activity;protein binding;calmodulin binding;high voltage-gated calcium channel activity;metal ion binding