GeneBe

CACNA1H

protein-coding

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

Gene summary

This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization and consist of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. The alpha-1 subunit has 24 transmembrane segments and forms the pore through which ions pass into the cell. There are multiple isoforms of each of the proteins in the complex, either encoded by different genes or the result of alternative splicing of transcripts. Alternate transcriptional splice variants, encoding different isoforms, have been characterized for the gene described here. Studies suggest certain mutations in this gene lead to childhood absence epilepsy (CAE). [provided by RefSeq, Jul 2008]

MANE transcript

NM_021098.3

Inheritance

AD

ClinVar variants

P:12U:1472B:1926

Top phenotype

Hyperaldosteronism, familial, type IV

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr16:1,153,103-1,224,169

External References & Databases

Ensembl (ENSG00000196557)NCBI Gene (8912)OMIM (607904)HGNC:1395GenCCUniProt (O95180)AlphaFoldClinVar (CACNA1H)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~71.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epilepsy, childhood absence, susceptibility to, 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012763

Submitter: G2P

hyperaldosteronism, familial, type IVSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014875

Submitter: Labcorp Genetics (formerly Invitae)

epilepsy, childhood absence, susceptibility to, 6LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012763

Submitter: Labcorp Genetics (formerly Invitae)

childhood absence epilepsySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010826

Submitter: Orphanet

Clinical Genomic Database (CGD)

Hyperaldosteronism, familial, type IVAD

Manifestation: Endocrine; Neurologic

Intervention: Endocrine

Rationale: Individuals may have severe hypertension, and awareness may allow medical (and possibly surgical, with adrenalectomy) treatment

Refs: 12891677; 15048902; 17696120; 25907736Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CACNA1H variants in ClinVar

18 Conditions Cataloged
Hyperaldosteronism, familial, type IVTotal: 3610
Idiopathic generalized epilepsyTotal: 3412
Epilepsy, childhood absence, susceptibility to, 6Total: 1020
not providedTotal: 649
not specifiedTotal: 635
Inborn genetic diseasesTotal: 585
CACNA1H-related disorderTotal: 166
See casesTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021098.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
23
clinvar
1051
clinvar
103
clinvar
 1177
missense
2
clinvar
7
clinvar
1360
clinvar
649
clinvar
122
clinvar
 2140
nonsense
3
clinvar
26
clinvar
 29
start loss
0
frameshift
47
clinvar
1
clinvar
 48
splice donor/acceptor (+/-2bp)
16
clinvar
 16
Total210147217012253410

Highest pathogenic variant AF is 0.000021084068

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 56 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_021098.3RefSeqNP_066921.234MANE Select
ENST00000348261.11EnsemblENSP00000334198.734MANE Select
NM_001005407.2RefSeqNP_001005407.133Standard
ENST00000562079.6EnsemblENSP00000454581.233Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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)

Biological Process

  • muscle contraction
  • muscle organ development
  • myoblast fusion
  • regulation of heart contraction
  • neuronal action potential

Molecular Function

  • voltage-gated ion channel activity
  • protein binding
  • low voltage-gated calcium channel activity
  • metal ion binding
  • scaffold protein binding

Cellular Component

  • plasma membrane
  • integral component of plasma membrane
  • voltage-gated calcium channel complex
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000348261
Coding exons
34
Length
68531
Individuals with no LoFs
124689
Homozygous LoFs
0
Heterozygous LoFs
37
Defined
124726
p
0.000148
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-2.3617171.46e+31.170.00010514893
Missense (PolyPhen)741726.91.01947451
Synonymous-13.010766531.650.00005244859
Loss of Function5.353285.30.3750.00000430944

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000650.000064rare
Latino/Admixed American0.000180.00017rare
Ashkenazi Jewish0.000100.000099rare
East Asian0.000170.00017rare
Finnish0.0000510.000046rare
European (Non-Finnish)0.000210.00017rare
South Asian0.0000990.000098rare
Other0.000690.00049rare

dbNSFP Gene Annotations

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.;

Recessive Scores

pRec
0.158

Intolerance Scores

LoFtool
0.00510
RVIS EVS
-2.06
RVIS percentile EVS
1.63

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.723

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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