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
Phenotypes
GenCC
Source:
- 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:
| 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
- Malignant hyperthermia, susceptibility to, 5;Hypokalemic periodic paralysis, type 1 (30 variants)
- Hypokalemic periodic paralysis, type 1;Malignant hyperthermia, susceptibility to, 5 (20 variants)
- not provided (7 variants)
- Hypokalemic periodic paralysis, type 1 (4 variants)
- Congenital myopathy 18 (3 variants)
- Malignant hyperthermia, susceptibility to, 5 (2 variants)
- Abnormality of the musculature (1 variants)
- Malignant hyperthermia, susceptibility to, 5;Thyrotoxic periodic paralysis, susceptibility to, 1;Hypokalemic periodic paralysis, type 1 (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.
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 | 16 | 543 | 20 | 579 | ||
| missense | 897 | 71 | 21 | 1005 | ||
| nonsense | 20 | 10 | 38 | |||
| start loss | 1 | |||||
| frameshift | 27 | 17 | 51 | |||
| inframe indel | 18 | 18 | ||||
| splice donor/acceptor (+/-2bp) | 21 | 11 | 32 | |||
| splice region | 75 | 96 | 7 | 178 | ||
| non coding | 21 | 345 | 86 | 452 | ||
| Total | 56 | 44 | 989 | 960 | 127 |
Highest pathogenic variant AF is 0.0000131
Variants in CACNA1S
This is a list of pathogenic ClinVar variants found in the CACNA1S region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 1-201039521-T-A | Hypokalemic periodic paralysis, type 1 • Thyrotoxic periodic paralysis, susceptibility to, 1 • Congenital myopathy 18 • Malignant hyperthermia, susceptibility to, 5 | Benign/Likely benign (Apr 11, 2023) | ||
| 1-201039571-A-T | Malignant hyperthermia of anesthesia • Hypokalemic periodic paralysis | Uncertain significance (Jun 14, 2016) | ||
| 1-201039579-A-G | Hypokalemic periodic paralysis, type 1 | Uncertain significance (Jan 13, 2018) | ||
| 1-201039648-G-A | Hypokalemic periodic paralysis, type 1 | Uncertain significance (Jan 13, 2018) | ||
| 1-201039661-C-T | Hypokalemic periodic paralysis, type 1 | Uncertain significance (Jan 12, 2018) | ||
| 1-201039668-C-T | Hypokalemic periodic paralysis, type 1 | Likely benign (Jan 12, 2018) | ||
| 1-201039697-C-A | Hypokalemic periodic paralysis, type 1 | Uncertain significance (Jan 13, 2018) | ||
| 1-201039722-C-A | Malignant hyperthermia of anesthesia • Hypokalemic periodic paralysis | Uncertain significance (Jun 14, 2016) | ||
| 1-201039727-A-G | Hypokalemic periodic paralysis, type 1 | Likely benign (Apr 27, 2017) | ||
| 1-201039744-C-T | Hypokalemic periodic paralysis, type 1 | Uncertain significance (Jan 12, 2018) | ||
| 1-201039831-T-C | Malignant hyperthermia, susceptibility to, 5 | Uncertain significance (Jan 11, 2024) | ||
| 1-201039832-C-A | Malignant hyperthermia, susceptibility to, 5;Hypokalemic periodic paralysis, type 1 | Uncertain significance (Jul 12, 2021) | ||
| 1-201039833-A-G | Uncertain significance (Sep 16, 2018) | |||
| 1-201039839-T-C | Malignant hyperthermia, susceptibility to, 5;Hypokalemic periodic paralysis, type 1 | Uncertain significance (Jan 22, 2023) | ||
| 1-201039840-T-C | Hypokalemic periodic paralysis, type 1;Malignant hyperthermia, susceptibility to, 5 • Malignant hyperthermia, susceptibility to, 5 | Likely benign (Oct 02, 2023) | ||
| 1-201039841-G-A | Hypokalemic periodic paralysis, type 1;Malignant hyperthermia, susceptibility to, 5 • Malignant hyperthermia, susceptibility to, 5 | Uncertain significance (Aug 08, 2023) | ||
| 1-201039842-G-A | Hypokalemic periodic paralysis, type 1;Malignant hyperthermia, susceptibility to, 5 • Malignant hyperthermia, susceptibility to, 5 | Uncertain significance (Sep 17, 2023) | ||
| 1-201039847-A-G | Hypokalemic periodic paralysis, type 1;Malignant hyperthermia, susceptibility to, 5 | Uncertain significance (Mar 18, 2022) | ||
| 1-201039852-GGTCTCC-G | Malignant hyperthermia, susceptibility to, 5;Hypokalemic periodic paralysis, type 1 | Uncertain significance (Dec 20, 2022) | ||
| 1-201039859-TG-T | Hypokalemic periodic paralysis, type 1;Malignant hyperthermia, susceptibility to, 5 | Uncertain significance (Dec 25, 2023) | ||
| 1-201039861-G-A | Malignant hyperthermia, susceptibility to, 5;Hypokalemic periodic paralysis, type 1 • Hypokalemic periodic paralysis, type 1 • Thyrotoxic periodic paralysis, susceptibility to, 1 • Malignant hyperthermia, susceptibility to, 5 • Congenital myopathy 18 | Likely benign (Dec 30, 2023) | ||
| 1-201039866-C-T | Hypokalemic periodic paralysis, type 1;Malignant hyperthermia, susceptibility to, 5 | Uncertain significance (Feb 07, 2023) | ||
| 1-201039870-G-A | Hypokalemic periodic paralysis, type 1;Malignant hyperthermia, susceptibility to, 5 • Malignant hyperthermia, susceptibility to, 5 | Likely benign (Aug 15, 2023) | ||
| 1-201039870-G-C | Hypokalemic periodic paralysis, type 1;Malignant hyperthermia, susceptibility to, 5 • Malignant hyperthermia, susceptibility to, 5 | Uncertain significance (Dec 13, 2023) | ||
| 1-201039877-T-C | Malignant hyperthermia, susceptibility to, 5;Hypokalemic periodic paralysis, type 1 • Hypokalemic periodic paralysis, type 1 • Malignant hyperthermia, susceptibility to, 5;Hypokalemic periodic paralysis, type 1;Thyrotoxic periodic paralysis, susceptibility to, 1 • Malignant hyperthermia, susceptibility to, 5 • Thyrotoxic periodic paralysis, susceptibility to, 1 • Congenital myopathy 18 | Uncertain significance (Nov 20, 2023) |
GnomAD
Source:
| 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:
- 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