CACNA1D
protein-codingcalcium voltage-gated channel subunit alpha1 D, the group of Calcium voltage-gated channel alpha1 subunits
Gene summary
Voltage-dependent 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, and gene expression. Calcium channels are multisubunit complexes composed of alpha-1, beta, alpha-2/delta, and gamma subunits. The channel activity is directed by the pore-forming alpha-1 subunit, whereas the others act as auxiliary subunits regulating this activity. The distinctive properties of the calcium channel types are related primarily to the expression of a variety of alpha-1 isoforms, namely alpha-1A, B, C, D, E, and S. This gene encodes the alpha-1D subunit. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2012]
- CCHL1A2
- CACNL1A2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~484.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014200
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0014200
Submitter: Illumina
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
The *CACNA1D* gene encodes the alpha-1D subunit of voltage-dependent calcium channels, which mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including hormone or neurotransmitter release, and gene expression. *CACNA1D* was first reported in relation to autosomal dominant complex neurodevelopmental disorder with or without aldosteronism in 2013 (Scholl et al., PMID: 23913001). This condition is characterized by developmental delay, intellectual disability, autism spectrum disorder, hypotonia and seizures (PMIDs: 32666275, 37122292). Other reported features include endocrine abnormalities such as primary aldosteronism and congenital hyperinsulinemic hypoglycemia, facial dysmorphisms, heart defects, and self-injurious behavior. *CACNA1D* has also been reported in relation to autosomal recessive sinoatrial node dysfunction and deafness; this disease has been curated separately. Nine missense variants reported in 11 probands in ten publications (PMIDs: 22495309, 22542183, 23913001, 25533962, 28318089, 28472301, 28726809, 32583268, 36208199, 37122292) are included in this curation. Most of the reported variants are *de novo*. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is gain of function (PMIDs: 23913001, 37122292). This gene-disease relationship is also supported by the biochemical function of CACNA1D, as seven other genes encoding alpha subunits of voltage-gated calcium channels have also been implicated in neurodevelopmental disorders, including *CACNA1A, CACNA1B, CACNA1C, CACNA1E, CACNA1G, CACNA1H, and CACNA1I*. In summary, there is definitive evidence supporting the relationship between CACNA1D and autosomal dominant complex neurodevelopmental disorder with or without aldosteronism. This has been repeatedly demonstrated in both research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on September 4, 2024 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0013960
Submitter: ClinGen
The *CACNA1D* gene was first associated with autosomal recessive sinoatrial node dysfunction and deafness in humans as early as 2011 (Baig et al., 2011, PMID: 21131953). Two unique founder variants (an in-frame indel and a missense) has been reported as homozygous occurrences in 9 individuals from consanguineous families across 3 publications (PMID: 21131953, 30498240, 32747562). Variants in this gene segregated with disease in at least 9 additional family members. This gene-disease relationship is supported by expression data, functional alteration studies, and mouse models (PMID: 21131953, 15357422, 10929716, 22678062). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the Hearing Loss GCEP on 5/1/2018. It was re-evaluated on 4/17/2024. Although new genetic evidence was included in the curation, the classification did not change (PMID: 30498240, 32747562). This classification was approved by the ClinGen Hearing Loss Working Group on the meeting date 4/17/2024 (SOP Version 10)
Inheritance Pattern: AD
Disease ID:MONDO:0014200
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013960
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013960
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014200
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013960
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Endocrine; Neurologic
Intervention: Audiologic/Otolaryngologic; Cardiovascular; Endocrine
Rationale: In Primary aldosteronism, seizures, and neurologic abnormalities, individuals may manifest with arrhythmias and other cardiac abnormalities, and awareness may allow prompt detection and treatment; Individuals may manifest with endocrine anomalies (eg, hypokalemia, hypoglycemia, hyperaldostorenemia), and awareness may allow early diagnosis and treatement, which has been described as benefitting some parameters; In Sinoatrial node dysfunction and deafness, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Individuals may demonstrate evidence of dysrhythmias (eg, manifesting with bradycardia, with syncopal episodes associated with and without physical activity and stress described), and surveillance (eg, with EKG) may be beneficial in order to allow early medical management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CACNA1D variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001128840.3. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 21 | 572 | 9 | 602 | ||
| missense | 3 | 15 | 1162 | 53 | 1233 | |
| nonsense | 1 | 1 | 20 | 22 | ||
| start loss | 0 | |||||
| frameshift | 1 | 30 | 31 | |||
| splice donor/acceptor (+/-2bp) | 1 | 2 | 33 | 36 | ||
| Total | 5 | 19 | 1266 | 625 | 9 | 1924 |
Highest pathogenic variant AF is 0.000016144777
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001122312.1 | 48 | MANE Select | |
| Ensembl | ENSP00000288133.5 | 48 | MANE Select | |
| RefSeq | NP_000711.1 | 49 | MANE Plus Clinical | |
| RefSeq | NP_001122311.1 | 46 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| cacna1da | Danio rerio | Structure: neuromast hair cell Quality: physical object quality abnormal |
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)
- Oxytocin signaling pathway - Homo sapiens (human)
- Retrograde endocannabinoid signaling - Homo sapiens (human)
- GABAergic synapse - Homo sapiens (human)
Biological Process
- calcium ion transport
- adenylate cyclase-modulating G protein-coupled receptor signaling pathway
- sensory perception of sound
- positive regulation of adenylate cyclase activity
- regulation of insulin secretion
Molecular Function
- voltage-gated calcium channel activity
- calcium channel activity
- high voltage-gated calcium channel activity
- ankyrin binding
- metal ion binding
Cellular Component
- plasma membrane
- voltage-gated calcium channel complex
- Z disc
- cochlear hair cell ribbon synapse
- integral component of presynaptic active zone membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000288139
- Coding exons
- 49
- Length
- 319078
- Individuals with no LoFs
- 125491
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 257
- Defined
- 125748
- p
- 0.00102
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.58 | 797 | 1.25e+3 | 0.636 | 0.0000792 | 14461 |
| Missense (PolyPhen) | 319 | 669.26 | 0.47665 | 7802 | ||
| Synonymous | -0.281 | 486 | 478 | 1.02 | 0.0000320 | 4130 |
| Loss of Function | 8.67 | 17 | 119 | 0.143 | 0.00000694 | 1347 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0019 | 0.0018 | notable |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0.00070 | 0.00069 | rare |
| East Asian | 0.0028 | 0.0027 | notable |
| Finnish | 0.00038 | 0.00037 | rare |
| European (Non-Finnish) | 0.0012 | 0.0012 | notable |
| South Asian | 0.00026 | 0.00026 | rare |
| Other | 0.0015 | 0.0015 | notable |
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-1D gives rise to L-type calcium currents. Long-lasting (L-type) calcium channels belong to the 'high-voltage activated' (HVA) group. They are blocked by dihydropyridines (DHP), phenylalkylamines, and by benzothiazepines. {ECO:0000269|PubMed:18482979, ECO:0000269|PubMed:25620733, ECO:0000269|PubMed:28472301}.;
- Disease
- DISEASE: Sinoatrial node dysfunction and deafness (SANDD) [MIM:614896]: A disease characterized by congenital severe to profound deafness without vestibular dysfunction, associated with episodic syncope due to intermittent pronounced bradycardia. {ECO:0000269|PubMed:21131953}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Primary aldosteronism, seizures, and neurologic abnormalities (PASNA) [MIM:615474]: A disorder characterized by hypertension, hypokalemia, and high aldosterone levels with low plasma renin activity and an elevated aldosterone/renin ratio. Other features include generalized seizures, cerebral palsy, spasticity, intellectual disability, and developmental delay. {ECO:0000269|PubMed:23913001}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Gain of function variations affecting the gene represented in this entry may be associated with susceptibility to autism spetrum disorders. {ECO:0000269|PubMed:22495309, ECO:0000269|PubMed:22542183, ECO:0000269|PubMed:25620733, ECO:0000269|PubMed:28472301}.;
Recessive Scores
- pRec
- 0.146
Intolerance Scores
- LoFtool
- 0.00420
- RVIS EVS
- -3.51
- RVIS percentile EVS
- 0.32
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.724
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |