CACNA1G
protein-codingcalcium voltage-gated channel subunit alpha1 G, the group of Calcium voltage-gated channel alpha1 subunits
Gene summary
Voltage-sensitive calcium channels 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. This gene encodes a T-type, low-voltage activated calcium channel. The T-type channels generate currents that are both transient, owing to fast inactivation, and tiny, owing to small conductance. T-type channels are thought to be involved in pacemaker activity, low-threshold calcium spikes, neuronal oscillations and resonance, and rebound burst firing. Many alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Sep 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~66.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0060758
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014776
Submitter: ClinGen
*CACNA1G* is located on chromosome 17 at 17q21.33 and encodes the calcium voltage-gated channel subunit alpha 1G protein, the pore-forming subunit of the low-voltage-activated (T-type) Cav3.1 channel. Variants in *CACNA1G* have been reported in individuals with the following disease entities: spinocerebellar ataxia 42 (OMIM:616795) and spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits (OMIM: 618087). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found insufficient functional evidence to distinguish the molecular mechanism of disease. Therefore, these twodisease entities have been lumped into one disease entity spinocerebellar ataxia 42 (OMIM:616795). *CACNA1G* was first reported in relation to autosomal dominant spinocerebellar ataxia 42 in 2015 (Morino et al., PMID 26715324). It is characterized by slowly progressive gait instability, dysarthria, pyramidal signs, nystagmus, and cerebellar atrophy. The age at onset and severity of the disorder is highly variable. Additionally, some individuals present with spinocerebellar ataxia 42, early-onset, severe, with neurodevelopmental deficits (SCA42ND) which is characterized by severe hypotonia, delayed psychomotor development with severe intellectual disability, absent speech, variable spasticity, dysmorphic features, and epileptic encephalopathy. SCA42ND is typically caused by de novo variants. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. At least seven unique missense variants have been reported in 25 individuals/families from 10 publications (PMIDs: 26715324, 31229688, 28490766, 29629410, 30200108, 34248568, 33098379, 32736238, 29878067, 3287833). Variants in this gene segregated with disease in nine families presenting with spinocerebellar ataxia 42 without neurodevelopmental deficits. This gene-disease relationship is supported by experimental data including expression studies, in vitro functional assays, and an animal model. *CACNA1G* is expressed in subsets of neurons (PMID: 18853439). Both heterozygous and homozygous knock-in mice show motor impairments due to ataxia and degenerative change of Purkinje cells (PMID 31229688). The mechanism of disease remains unclear with variants demonstrating either gain-of-function, loss-of-function, or mixed effects due to the opposing shifts of the activation and inactivation curves of Ca2+ currents conducted on patient variants in in vitro functional assays (PMID: 32878331). In summary, there is definitive evidence to support the relationship between *CACNA1G* and autosomal dominant spinocerebellar ataxia 42. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date December 4th, 2024 (SOP Version 11).
Inheritance Pattern: AD
Disease ID:MONDO:0014776
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0014776
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0060758
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0060758
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014776
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014776
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0001071
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0060758
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014776
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0700092
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014776
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CACNA1G variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_018896.5. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 19 | 228 | 32 | 279 | ||
| missense | 2 | 30 | 707 | 167 | 9 | 915 |
| nonsense | 1 | 17 | 18 | |||
| start loss | 1 | 1 | ||||
| frameshift | 22 | 1 | 23 | |||
| splice donor/acceptor (+/-2bp) | 7 | 1 | 8 | |||
| Total | 2 | 31 | 773 | 397 | 41 | 1244 |
Highest pathogenic variant AF is 0.00003534042
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_061496.2 | 38 | MANE Select | |
| Ensembl | ENSP00000352011.5 | 38 | MANE Select | |
| RefSeq | NP_001243253.1 | 36 | Standard | |
| RefSeq | NP_001243254.1 | 36 | Standard |
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)
- Type II diabetes mellitus - Homo sapiens (human)
- Cushing,s syndrome - Homo sapiens (human)
- Circadian entrainment - Homo sapiens (human)
Biological Process
- chemical synaptic transmission
- response to nickel cation
- neuronal action potential
- regulation of ion transmembrane transport
- regulation of membrane potential
Molecular Function
- low voltage-gated calcium channel activity
- voltage-gated calcium channel activity involved in AV node cell action potential
- voltage-gated calcium channel activity involved SA node cell action potential
- scaffold protein binding
Cellular Component
- cytoplasm
- plasma membrane
- voltage-gated calcium channel complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000359106
- Coding exons
- 38
- Length
- 66407
- Individuals with no LoFs
- 124595
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 85
- Defined
- 124680
- p
- 0.000341
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.64 | 963 | 1.46e+3 | 0.659 | 0.0000932 | 15335 |
| Missense (PolyPhen) | 205 | 618.63 | 0.33138 | 6687 | ||
| Synonymous | 0.977 | 602 | 633 | 0.951 | 0.0000424 | 4868 |
| Loss of Function | 7.95 | 13 | 97.9 | 0.133 | 0.00000516 | 1067 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00028 | 0.00026 | rare |
| Latino/Admixed American | 0.00021 | 0.00020 | rare |
| Ashkenazi Jewish | 0.0014 | 0.0013 | notable |
| East Asian | 0.00018 | 0.00017 | rare |
| Finnish | 0.00011 | 0.000093 | rare |
| European (Non-Finnish) | 0.00042 | 0.00039 | rare |
| South Asian | 0.00031 | 0.00029 | rare |
| Other | 0.00055 | 0.00050 | rare |
dbNSFP Gene Annotations
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-1G gives rise to T-type calcium currents. T-type calcium channels belong to the "low-voltage activated (LVA)" group and are strongly blocked by mibefradil. A particularity of this type of channel is an opening at quite negative potentials and a voltage-dependent inactivation. 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. They may also be involved in the modulation of firing patterns of neurons which is important for information processing as well as in cell growth processes. {ECO:0000269|PubMed:10648811, ECO:0000269|PubMed:10692398, ECO:0000269|PubMed:26456284, ECO:0000269|PubMed:26715324}.;
- Disease
- DISEASE: Spinocerebellar ataxia 42 (SCA42) [MIM:616795]: A form of spinocerebellar ataxia, 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. SCA42 is a slowly progressive, autosomal dominant form with variable severity. {ECO:0000269|PubMed:26456284, ECO:0000269|PubMed:26715324}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.174
Intolerance Scores
- LoFtool
- 0.000620
- RVIS EVS
- -2.37
- RVIS percentile EVS
- 1.11
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.240
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |