CACNA1H

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

Basic information

Region (hg38): 16:1153105-1221771

Links

ENSG00000196557 ∙ NCBI:8912 ∙ OMIM:607904 ∙ HGNC:1395 ∙ Uniprot:O95180 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• childhood absence epilepsy (Supportive), mode of inheritance: AD
• epilepsy, childhood absence, susceptibility to, 6 (Limited), mode of inheritance: AD
• hyperaldosteronism, familial, type IV (Strong), mode of inheritance: AD
• epilepsy, childhood absence, susceptibility to, 6 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hyperaldosteronism, familial, type IV	AD	Endocrine	Individuals may have severe hypertension, and awareness may allow medical (and possibly surgical, with adrenalectomy) treatment	Endocrine; Neurologic	12891677; 15048902; 17696120; 25907736

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CACNA1H gene.

• Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV (1494 variants)
• Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy (1071 variants)
• not provided (545 variants)
• Epilepsy, childhood absence, susceptibility to, 6;Hyperaldosteronism, familial, type IV (395 variants)
• Inborn genetic diseases (249 variants)
• Hyperaldosteronism, familial, type IV;Epilepsy, childhood absence, susceptibility to, 6 (193 variants)
• not specified (56 variants)
• Epilepsy, childhood absence, susceptibility to, 6 (55 variants)
• Hyperaldosteronism, familial, type IV (22 variants)
• CACNA1H-related condition (10 variants)
• See cases (5 variants)
• Epilepsy, idiopathic generalized, susceptibility to, 6 (2 variants)
• Hyperaldosteronism (2 variants)
• Abnormal brain morphology (2 variants)
• Focal epilepsy (1 variants)
• CACNA1H-related disorder (1 variants)
• Idiopathic generalized epilepsy;Epilepsy, childhood absence, susceptibility to, 6 (1 variants)
• Primary aldosteronism (1 variants)
• Breast ductal adenocarcinoma (1 variants)
• Seizure (1 variants)
• Arteriovenous malformation;Cerebral arteriovenous malformation;Tremor;Hand tremor (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CACNA1H 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			24	751	81	856
missense	1	5	902	113	174	1195
nonsense		2	13			15
start loss						0
frameshift			13			13
inframe indel			33	2	1	36
splice donor/acceptor (+/-2bp)			8		1	9
splice region			60	106	13	179
non coding			12	278	109	399
Total	1	7	1005	1144	366

Highest pathogenic variant AF is 0.0000132

Variants in CACNA1H

This is a list of pathogenic ClinVar variants found in the CACNA1H region.

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

Position	Type	Phenotype	Significance	ClinVar
16-1153321-CGGGCCGGGGGCGGAGGCGCTGGGGGCCGGGGCCG-C			Benign (Mar 04, 2021)
16-1153742-C-A		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV	Uncertain significance (Nov 08, 2022)
16-1153743-C-T		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV	Likely benign (Nov 11, 2023)
16-1153750-G-A		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV • Inborn genetic diseases	Conflicting classifications of pathogenicity (Dec 23, 2023)
16-1153750-G-T		Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy	Benign (Nov 19, 2022)
16-1153752-A-C		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV	Likely benign (Jul 26, 2022)
16-1153753-C-A		Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy	Likely benign (Aug 06, 2020)
16-1153754-G-A		Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy	Uncertain significance (Aug 05, 2022)
16-1153758-C-A		Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy	Likely benign (Apr 26, 2020)
16-1153758-C-G		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV	Likely benign (Dec 02, 2022)
16-1153758-C-T		Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy • Epilepsy, childhood absence, susceptibility to, 6;Hyperaldosteronism, familial, type IV	Likely benign (Aug 17, 2023)
16-1153765-G-A		Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy	Uncertain significance (Dec 12, 2023)
16-1153768-G-C			Uncertain significance (Jan 01, 2023)
16-1153773-G-C		Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy	Likely benign (Nov 24, 2023)
16-1153776-G-A		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV	Likely benign (Aug 08, 2019)
16-1153777-C-T		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV	Uncertain significance (Jul 14, 2022)
16-1153778-C-T		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV • Epilepsy, childhood absence, susceptibility to, 6;Hyperaldosteronism, familial, type IV	Conflicting classifications of pathogenicity (Mar 30, 2023)
16-1153779-C-T		Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy	Likely benign (Feb 22, 2021)
16-1153780-C-T		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV • Epilepsy, childhood absence, susceptibility to, 6;Hyperaldosteronism, familial, type IV	Likely benign (Sep 28, 2023)
16-1153785-C-T		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV	Uncertain significance (Sep 09, 2020)
16-1153789-C-T		Inborn genetic diseases	Uncertain significance (Mar 24, 2023)
16-1153791-G-A		Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy	Likely benign (Nov 24, 2023)
16-1153791-G-T		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV	Likely benign (Sep 15, 2023)
16-1153793-C-G		Idiopathic generalized epilepsy;Hyperaldosteronism, familial, type IV	Uncertain significance (Nov 03, 2020)
16-1153796-C-G		Hyperaldosteronism, familial, type IV;Idiopathic generalized epilepsy	Uncertain significance (Jan 11, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CACNA1H	protein_coding	protein_coding	ENST00000348261	34	68531

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.78e-10	1.00	124689	0	37	124726	0.000148

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-2.36	1717	1.46e+3	1.17	0.000105	14893
Missense in Polyphen		741	726.9	1.0194		7451
Synonymous	-13.0	1076	653	1.65	0.0000524	4859
Loss of Function	5.35	32	85.3	0.375	0.00000430	944

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000243	0.000242
Ashkenazi Jewish	0.000101	0.0000994
East Asian	0.000168	0.000167
Finnish	0.0000508	0.0000464
European (Non-Finnish)	0.000205	0.000168
Middle Eastern	0.000168	0.000167
South Asian	0.0000987	0.0000980
Other	0.000686	0.000495

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Voltage-sensitive calcium channel that gives rise to T- type calcium currents. T-type calcium channels belong to the "low- voltage activated (LVA)" group. A particularity of this type of channel is an opening at quite negative potentials, and a voltage- dependent inactivation (PubMed:9670923, PubMed:9930755, PubMed:27149520). T-type channels serve pacemaking functions in both central neurons and cardiac nodal cells and support calcium signaling in secretory cells and vascular smooth muscle (Probable). They may also be involved in the modulation of firing patterns of neurons (PubMed:15048902). In the adrenal zona glomerulosa, participates in the signaling pathway leading to aldosterone production in response to either AGT/angiotensin II, or hyperkalemia (PubMed:25907736, PubMed:27729216). {ECO:0000269|PubMed:25907736, ECO:0000269|PubMed:27149520, ECO:0000269|PubMed:27729216, ECO:0000269|PubMed:9670923, ECO:0000269|PubMed:9930755, ECO:0000305, ECO:0000305|PubMed:15048902}.
• Disease: DISEASE: Epilepsy, idiopathic generalized 6 (EIG6) [MIM:611942]: A disorder characterized by recurring generalized seizures in the absence of detectable brain lesions and/or metabolic abnormalities. Generalized seizures arise diffusely and simultaneously from both hemispheres of the brain. {ECO:0000269|PubMed:15048902}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Epilepsy, childhood absence 6 (ECA6) [MIM:611942]: A subtype of idiopathic generalized epilepsy characterized by an onset at age 6-7 years, frequent absence seizures (several per day) and bilateral, synchronous, symmetric 3-Hz spike waves on EEG. Tonic-clonic seizures often develop in adolescence. Absence seizures may either remit or persist into adulthood. {ECO:0000269|PubMed:12891677}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Hyperaldosteronism, familial, 4 (HALD4) [MIM:617027]: A form of familial hyperaldosteronism, a disorder characterized by hypertension, elevated aldosterone levels despite low plasma renin activity, and abnormal adrenal steroid production. There is significant phenotypic heterogeneity, and some individuals never develop hypertension. {ECO:0000269|PubMed:25907736, ECO:0000269|PubMed:27729216}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Cortisol synthesis and secretion - Homo sapiens (human);Aldosterone synthesis and secretion - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Celecoxib Pathway, Pharmacodynamics;Antiarrhythmic Pathway, Pharmacodynamics;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Bupranolol Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Corticotropin-releasing hormone signaling pathway;MAPK Signaling Pathway;Developmental Biology;NCAM signaling for neurite out-growth;NCAM1 interactions;Axon guidance (Consensus)

Recessive Scores

• pRec: 0.158

Intolerance Scores

• loftool: 0.00510
• rvis_EVS: -2.06
• rvis_percentile_EVS: 1.63

Haploinsufficiency Scores

• pHI: 0.121
• hipred: Y
• hipred_score: 0.649
• ghis: 0.555

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.723

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cacna1h
• 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); skeleton phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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); muscle phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: muscle contraction;muscle organ development;myoblast fusion;regulation of heart contraction;neuronal action potential;aldosterone biosynthetic process;cellular response to hormone stimulus;cortisol biosynthetic process;regulation of ion transmembrane transport;cellular response to potassium ion;regulation of membrane potential;positive regulation of calcium ion-dependent exocytosis;calcium ion import;calcium ion transmembrane transport;membrane depolarization during action potential;inorganic cation transmembrane transport;positive regulation of acrosome reaction
• Cellular component: plasma membrane;integral component of plasma membrane;voltage-gated calcium channel complex;integral component of membrane
• Molecular function: voltage-gated ion channel activity;protein binding;low voltage-gated calcium channel activity;metal ion binding;scaffold protein binding