CACNA1A
calcium voltage-gated channel subunit alpha1 A, the group of Calcium voltage-gated channel alpha1 subunits
Basic information
Region (hg38): 19:13206442-13624489
Previous symbols: [ "CACNL1A4", "SCA6", "MHP1", "MHP" ]
Links
Phenotypes
GenCC
Source:
- migraine, familial hemiplegic, 1 (Strong), mode of inheritance: AD
- episodic ataxia type 2 (Strong), mode of inheritance: AD
- spinocerebellar ataxia type 6 (Strong), mode of inheritance: AD
- spinocerebellar ataxia type 6 (Strong), mode of inheritance: AD
- episodic ataxia type 2 (Definitive), mode of inheritance: AD
- developmental and epileptic encephalopathy, 42 (Moderate), mode of inheritance: AD
- migraine, familial hemiplegic, 1 (Strong), mode of inheritance: AD
- episodic ataxia type 2 (Supportive), mode of inheritance: AD
- Lennox-Gastaut syndrome (Supportive), mode of inheritance: AD
- familial or sporadic hemiplegic migraine (Supportive), mode of inheritance: AD
- benign paroxysmal torticollis of infancy (Supportive), mode of inheritance: AD
- spinocerebellar ataxia type 6 (Supportive), mode of inheritance: AD
- undetermined early-onset epileptic encephalopathy (Supportive), mode of inheritance: AD
- undetermined early-onset epileptic encephalopathy (Definitive), mode of inheritance: AD
- episodic ataxia type 2 (Strong), mode of inheritance: AD
- developmental and epileptic encephalopathy, 42 (Strong), mode of inheritance: AD
- migraine, familial hemiplegic, 1 (Strong), mode of inheritance: AD
- spinocerebellar ataxia type 6 (Strong), mode of inheritance: AD
- developmental and epileptic encephalopathy, 42 (Strong), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Episodic ataxia, type 2; Migraine, familial hemiplegic 1; Spinocerebellar ataxia 6 | AD | Neurologic; Pharmacogenomic | Medical treatment (eg, 4-aminopyridine, acetazolamide, as well as other standard migraine-related medications to treat migraines) may be effective; In Migraine, familial hemiplegic 1, vasoconstricting agents (due to risk of stroke) and cerebral angiography (due to risk of precipitation of attack) should be avoided; In Spinocerebellar ataxia 6, ataxia may be managed medically (with acetazolamide); Vestibular symptoms may be managed medically (eg, with diphenhydramine, baclofen, and gabapentin. 4-aminopyridine) | Neurologic | 6684259; 3469025; 1575453; 7757080; 8898206; 14681882; 9311738; 9302278; 9259274; 9259275; 8734765 ; 9403486; 9345107; 8988170; 15210532; 9915947; 10668728; 11439943; 11673601; 12081723; 12056940; 12707077; 14681882; 14718690; 15136697; 15362569; 16186543; 15710862; 15747371; 17575281; 17142831; 18541804; 18685131; 20301319; 20301562; 19633872; 21734179; 20837964; 23934111; 27476654; 28856914; 31824404 |
ClinVar
This is a list of variants' phenotypes submitted to
- Developmental_and_epileptic_encephalopathy,_42 (2871 variants)
- Episodic_ataxia_type_2 (2863 variants)
- not_provided (1725 variants)
- Inborn_genetic_diseases (498 variants)
- not_specified (336 variants)
- CACNA1A-related_disorder (201 variants)
- Migraine,_familial_hemiplegic,_1 (152 variants)
- Spinocerebellar_ataxia_type_6 (148 variants)
- Developmental_and_epileptic_encephalopathy,_52 (33 variants)
- Intellectual_disability (13 variants)
- Familial_hemiplegic_migraine (9 variants)
- CACNA1A-related_complex_neurodevelopmental_disorder (7 variants)
- Seizure (7 variants)
- Tip-toe_gait (6 variants)
- Neurodevelopmental_delay (6 variants)
- Cerebellar_ataxia (6 variants)
- Global_developmental_delay (5 variants)
- See_cases (4 variants)
- Hereditary_episodic_ataxia (4 variants)
- Developmental_and_epileptic_encephalopathy,_1 (3 variants)
- Epileptic_encephalopathy (3 variants)
- Autism_spectrum_disorder (2 variants)
- Neurodevelopmental_abnormality (2 variants)
- Alternating_hemiplegia_of_childhood_1 (2 variants)
- Early_Infantile_Epileptic_Encephalopathy,_Autosomal_Dominant (2 variants)
- Idiopathic_hemiconvulsion-hemiplegia_syndrome (1 variants)
- Chronic_and_progressive_ataxia (1 variants)
- Chorea (1 variants)
- Lennox-Gastaut_syndrome (1 variants)
- EEG_with_focal_epileptiform_discharges (1 variants)
- Bulbar_palsy (1 variants)
- Focal_epilepsy (1 variants)
- Neurodevelopmental_disorder (1 variants)
- Strabismus (1 variants)
- Delayed_gross_motor_development (1 variants)
- Generalized_hypotonia (1 variants)
- Abnormality_of_the_nervous_system (1 variants)
- Sporadic_hemiplegic_migraine (1 variants)
- Migraine,_sporadic_hemiplegic,_with_progressive_cerebellar_ataxia (1 variants)
- Intention_tremor (1 variants)
- Dysarthria (1 variants)
- Developmental_and_epileptic_encephalopathy,_2 (1 variants)
- Cerebellar_atrophy (1 variants)
- Ataxia___Neurologic_(child_onset) (1 variants)
- Epilepsy (1 variants)
- Disorder_of_sexual_differentiation (1 variants)
- Spastic_paraparesis (1 variants)
- Non-progressive_congenital_cerebellar_ataxia (1 variants)
- Mild_global_developmental_delay (1 variants)
- Recurrent_respiratory_infections (1 variants)
- Amyotrophic_lateral_sclerosis (1 variants)
- Hereditary_ataxia (1 variants)
- CACNA1A-associated_disorder (1 variants)
- Subependymal_giant-cell_astrocytoma (1 variants)
- CACNA1A-associated_disorders (1 variants)
- Vascular_dementia (1 variants)
- Undetermined_early-onset_epileptic_encephalopathy (1 variants)
- Cerebral_palsy (1 variants)
- Migraine (1 variants)
- Enlarged_cisterna_magna (1 variants)
- Spastic_ataxia (1 variants)
- SUDDEN_INFANT_DEATH_SYNDROME (1 variants)
- Febrile_seizure (1 variants)
- Episodic_ataxia,_type_2,_and_epilepsy (1 variants)
- Gait_ataxia (1 variants)
- Hereditary_cerebellar_ataxia (1 variants)
- Auditory_neuropathy (1 variants)
- Neurodevelopmental_disorder_with_hypotonia,_language_delay,_and_skeletal_defects_with_or_without_seizures (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the CACNA1A gene is commonly pathogenic or not. These statistics are base on transcript: NM_001127222.2. 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 | 33 | 766 | 22 | 821 | ||
| missense | 50 | 155 | 1460 | 285 | 1959 | |
| nonsense | 74 | 28 | 105 | |||
| start loss | 1 | 1 | ||||
| frameshift | 137 | 49 | 17 | 203 | ||
| splice donor/acceptor (+/-2bp) | 18 | 51 | 72 | |||
| Total | 280 | 283 | 1516 | 1051 | 31 |
Highest pathogenic variant AF is 0.000116978
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| CACNA1A | protein_coding | protein_coding | ENST00000360228 | 47 | 417549 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 4.32e-13 | 124643 | 0 | 12 | 124655 | 0.0000481 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 5.78 | 844 | 1.47e+3 | 0.575 | 0.0000976 | 16214 |
| Missense in Polyphen | 159 | 372.91 | 0.42638 | 3690 | ||
| Synonymous | -0.260 | 621 | 613 | 1.01 | 0.0000449 | 4918 |
| Loss of Function | 9.27 | 9 | 117 | 0.0767 | 0.00000664 | 1264 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0000665 | 0.0000646 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.0000556 | 0.0000556 |
| Finnish | 0.00 | 0.00 |
| European (Non-Finnish) | 0.0000844 | 0.0000796 |
| Middle Eastern | 0.0000556 | 0.0000556 |
| South Asian | 0.0000338 | 0.0000327 |
| Other | 0.00 | 0.00 |
dbNSFP
Source:
- Function
- FUNCTION: Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene expression, cell motility, cell division and cell death. The isoform alpha-1A gives rise to P and/or Q-type calcium currents. P/Q-type calcium channels belong to the 'high-voltage activated' (HVA) group and are specifically blocked by the spider omega-agatoxin-IVA (AC P54282) (By similarity). They are however insensitive to dihydropyridines (DHP). {ECO:0000250|UniProtKB:P54282, ECO:0000269|PubMed:10049321, ECO:0000269|PubMed:10753886, ECO:0000269|PubMed:11723274, ECO:0000269|PubMed:15293273, ECO:0000269|PubMed:19232643, ECO:0000269|PubMed:24836863, ECO:0000269|PubMed:26716990}.;
- Disease
- DISEASE: Spinocerebellar ataxia 6 (SCA6) [MIM:183086]: Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA6 is an autosomal dominant cerebellar ataxia (ADCA), mainly caused by expansion of a CAG repeat in the coding region of CACNA1A. There seems to be a correlation between the repeat number and earlier onset of the disorder. {ECO:0000269|PubMed:16325861, ECO:0000269|PubMed:20682717, ECO:0000269|PubMed:29053796, ECO:0000269|PubMed:8988170, ECO:0000269|PubMed:9302278, ECO:0000269|PubMed:9345107}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Migraine, familial hemiplegic, 1 (FHM1) [MIM:141500]: A subtype of migraine with aura associated with ictal hemiparesis and, in some families, cerebellar ataxia and atrophy. Migraine is a disabling symptom complex of periodic headaches, usually temporal and unilateral. Headaches are often accompanied by irritability, nausea, vomiting and photophobia, preceded by constriction of the cranial arteries. Migraine with aura is characterized by recurrent attacks of reversible neurological symptoms (aura) that precede or accompany the headache. Aura may include a combination of sensory disturbances, such as blurred vision, hallucinations, vertigo, numbness and difficulty in concentrating and speaking. {ECO:0000269|PubMed:10408532, ECO:0000269|PubMed:11409427, ECO:0000269|PubMed:11439943, ECO:0000269|PubMed:15032980, ECO:0000269|PubMed:18400034, ECO:0000269|PubMed:24836863, ECO:0000269|PubMed:26716990, ECO:0000269|PubMed:28900389, ECO:0000269|PubMed:8898206}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Episodic ataxia 2 (EA2) [MIM:108500]: An autosomal dominant disorder characterized by acetozolamide-responsive attacks of ataxia, migraine-like symptoms, interictal nystagmus, and cerebellar atrophy. {ECO:0000269|PubMed:10408533, ECO:0000269|PubMed:10987655, ECO:0000269|PubMed:11176968, ECO:0000269|PubMed:11723274, ECO:0000269|PubMed:12420090, ECO:0000269|PubMed:14718690, ECO:0000269|PubMed:15173248, ECO:0000269|PubMed:15293273, ECO:0000269|PubMed:18602318, ECO:0000269|PubMed:19232643, ECO:0000269|PubMed:20129625, ECO:0000269|PubMed:21696515, ECO:0000269|PubMed:8898206, ECO:0000269|PubMed:9302278}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Epileptic encephalopathy, early infantile, 42 (EIEE42) [MIM:617106]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE42 inheritance is autosomal dominant. {ECO:0000269|PubMed:27250579, ECO:0000269|PubMed:27476654}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
- Pathway
- Synaptic vesicle cycle - Homo sapiens (human);Retrograde endocannabinoid signaling - Homo sapiens (human);GABAergic synapse - Homo sapiens (human);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Type II diabetes mellitus - Homo sapiens (human);Long-term depression - Homo sapiens (human);Nicotine addiction - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Taste transduction - Homo sapiens (human);Morphine addiction - Homo sapiens (human);Celecoxib Pathway, Pharmacodynamics;Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics;Sympathetic Nerve Pathway (Pre- and Post- Ganglionic Junction);Sympathetic Nerve Pathway (Neuroeffector Junction);Levomethadyl Acetate Action Action Pathway;Fluoxetine Action Pathway;Citalopram Action Pathway;Escitalopram Action Pathway;Imipramine Action Pathway;Desipramine Action Pathway;Levallorphan Action Pathway;Dimethylthiambutene Action Pathway;Ethylmorphine Action Pathway;Pentazocine Action Pathway;Naltrexone Action Pathway;Buprenorphine Action Pathway;Alvimopan Action Pathway;Naloxone Action Pathway;Dihydromorphine Action Pathway;Glibenclamide Action Pathway;Gliclazide Action Pathway;Nicotine Action Pathway;Nalbuphine Action Pathway;Ketobemidone Action Pathway;Lidocaine (Local Anaesthetic) Action Pathway;Mepivacaine Action Pathway;Chloroprocaine Action Pathway;Cocaine Action Pathway;Dibucaine Action Pathway;Levobupivacaine Action Pathway;Benzocaine Action Pathway;Bupivacaine Action Pathway;Levorphanol Action Pathway;Propoxyphene Action Pathway;Tramadol Action Action Pathway;Diphenoxylate Action Pathway;Anileridine Action Pathway;Methadone Action Pathway;Oxycodone Action Pathway;Oxybuprocaine Action Pathway;Prilocaine Action Pathway;Procaine Action Pathway;Proparacaine Action Pathway;Ropivacaine Action Pathway;Codeine Action Pathway;Morphine Action Pathway;Heroin Action Pathway;Pancreas Function;Alfentanil Action Pathway;Oxymorphone Action Pathway;Hydrocodone Action Pathway;Hydromorphone Action Pathway;Sufentanil Action Pathway;Remifentanil Action Pathway;Fentanyl Action Pathway;Carfentanil Action Pathway;Repaglinide Action Pathway;Nateglinide Action Pathway;3-Methylthiofentanyl Action Pathway;Methadyl Acetate Action Pathway;Dezocine Action Pathway;Type II diabetes mellitus;Synaptic Vesicle Pathway;MAPK Signaling Pathway;Calcium Regulation in the Cardiac Cell;pkc-catalyzed phosphorylation of inhibitory phosphoprotein of myosin phosphatase;rho cell motility signaling pathway;rac1 cell motility signaling pathway;Metabolism;Regulation of insulin secretion;Neuronal System;Presynaptic depolarization and calcium channel opening;Transmission across Chemical Synapses;Integration of energy metabolism
(Consensus)
Recessive Scores
- pRec
- 0.559
Intolerance Scores
- loftool
- rvis_EVS
- -1.78
- rvis_percentile_EVS
- 2.27
Haploinsufficiency Scores
- pHI
- 0.586
- hipred
- Y
- hipred_score
- 0.732
- ghis
- 0.600
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.731
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | Medium | Medium |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |
Mouse Genome Informatics
- Gene name
- Cacna1a
- Phenotype
- muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; hematopoietic system phenotype; growth/size/body region phenotype; reproductive system phenotype; 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); normal 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); 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); immune system phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan);
Zebrafish Information Network
- Gene name
- cacna1ab
- Affected structure
- slow muscle cell
- Phenotype tag
- abnormal
- Phenotype quality
- non-contractile
Gene ontology
- Biological process
- calcium ion transport;positive regulation of cytosolic calcium ion concentration;chemical synaptic transmission;cell death;regulation of ion transmembrane transport;regulation of insulin secretion;modulation of chemical synaptic transmission;membrane depolarization;calcium ion import;calcium ion transmembrane transport;response to amyloid-beta;cellular response to amyloid-beta
- Cellular component
- nucleus;cytoplasm;plasma membrane;voltage-gated calcium channel complex;integral component of membrane;cell projection;neuronal cell body
- Molecular function
- amyloid-beta binding;voltage-gated calcium channel activity;calcium channel activity;protein binding;high voltage-gated calcium channel activity;syntaxin binding;metal ion binding