CACNA1D
calcium voltage-gated channel subunit alpha1 D, the group of Calcium voltage-gated channel alpha1 subunits
Basic information
Region (hg38): 3:53328963-53813733
Previous symbols: [ "CCHL1A2", "CACNL1A2" ]
Links
Phenotypes
GenCC
Source:
- sinoatrial node dysfunction and deafness (Moderate), mode of inheritance: AR
- sinoatrial node dysfunction and deafness (Strong), mode of inheritance: AR
- aldosterone-producing adenoma with seizures and neurological abnormalities (Strong), mode of inheritance: AD
- aldosterone-producing adenoma with seizures and neurological abnormalities (Moderate), mode of inheritance: AD
- sinoatrial node dysfunction and deafness (Supportive), mode of inheritance: AR
- aldosterone-producing adenoma with seizures and neurological abnormalities (Definitive), mode of inheritance: AD
- aldosterone-producing adenoma with seizures and neurological abnormalities (Strong), mode of inheritance: AD
- sinoatrial node dysfunction and deafness (Strong), mode of inheritance: AR
- sinoatrial node dysfunction and deafness (Moderate), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Primary aldosteronism, seizures, and neurologic abnormalities; Sinoatrial node dysfunction and deafness | AD/AR | Audiologic/Otolaryngologic; Cardiovascular; Endocrine | 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 | Audiologic/Otolaryngologic; Cardiovascular; Endocrine; Neurologic | 21131953; 23913001 |
ClinVar
This is a list of variants' phenotypes submitted to
- not_provided (2054 variants)
- Inborn_genetic_diseases (174 variants)
- not_specified (158 variants)
- CACNA1D-related_disorder (70 variants)
- Aldosterone-producing_adenoma_with_seizures_and_neurological_abnormalities (65 variants)
- Sinoatrial_node_dysfunction_and_deafness (47 variants)
- Intellectual_disability (8 variants)
- Hearing_impairment (4 variants)
- See_cases (4 variants)
- Meniere_disease (2 variants)
- Congenital_anomaly_of_kidney_and_urinary_tract (2 variants)
- Dystonia,_early-onset,_and/or_spastic_paraplegia (1 variants)
- CACNA1D-related_neurodevelopmental_and_endocrine_disorders (1 variants)
- Autism_spectrum_disorder (1 variants)
- Congenital_long_QT_syndrome (1 variants)
- Congenital_disorder_of_glycosylation,_type_Iw,_autosomal_dominant (1 variants)
- EBV-positive_nodal_T-_and_NK-cell_lymphoma (1 variants)
- Prostate_cancer (1 variants)
- Autosomal_recessive_Alport_syndrome (1 variants)
- VATER_association (1 variants)
- Skeletal_dysplasia (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the CACNA1D gene is commonly pathogenic or not. These statistics are base on transcript: NM_001128840.3. 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 | 14 | 488 | 510 | |||
| missense | 10 | 939 | 51 | 1004 | ||
| nonsense | 19 | 20 | ||||
| start loss | 0 | |||||
| frameshift | 26 | 27 | ||||
| splice donor/acceptor (+/-2bp) | 20 | 23 | ||||
| Total | 5 | 13 | 1018 | 539 | 9 |
Highest pathogenic variant AF is 0.0000161448
Loading clinvar variants...
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| CACNA1D | protein_coding | protein_coding | ENST00000288139 | 49 | 319078 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 1.19e-7 | 125491 | 0 | 257 | 125748 | 0.00102 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 4.58 | 797 | 1.25e+3 | 0.636 | 0.0000792 | 14461 |
| Missense in 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 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00215 | 0.00202 |
| Ashkenazi Jewish | 0.000701 | 0.000695 |
| East Asian | 0.00278 | 0.00272 |
| Finnish | 0.000378 | 0.000370 |
| European (Non-Finnish) | 0.00125 | 0.00121 |
| Middle Eastern | 0.00278 | 0.00272 |
| South Asian | 0.000261 | 0.000261 |
| Other | 0.00151 | 0.00147 |
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-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}.;
- Pathway
- 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);Serotonergic synapse - Homo sapiens (human);Dopaminergic synapse - Homo sapiens (human);Cardiac muscle contraction - Homo sapiens (human);Glutamatergic synapse - Homo sapiens (human);Type II diabetes mellitus - Homo sapiens (human);Cushing,s syndrome - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Tight junction - Homo sapiens (human);GnRH signaling pathway - Homo sapiens (human);Alzheimer,s disease - Homo sapiens (human);Carbohydrate digestion and absorption - Homo sapiens (human);Circadian entrainment - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);cAMP signaling pathway - Homo sapiens (human);Vascular smooth muscle contraction - Homo sapiens (human);Renin secretion - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Amphetamine addiction - Homo sapiens (human);cGMP-PKG signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Cholinergic synapse - Homo sapiens (human);Insulin secretion - Homo sapiens (human);Celecoxib Pathway, Pharmacodynamics;Anti-diabetic Drug Potassium Channel Inhibitors Pathway, Pharmacodynamics;Valproic Acid Pathway, Pharmacodynamics;Pathway_PA165964473;Beta-agonist/Beta-blocker Pathway, Pharmacodynamics;Sympathetic Nerve Pathway (Pre- and Post- Ganglionic Junction);Antiarrhythmic Pathway, Pharmacodynamics;Sympathetic Nerve Pathway (Neuroeffector Junction);Alzheimers Disease;Arrhythmogenic Right Ventricular Cardiomyopathy;MAPK Signaling Pathway;Calcium Regulation in the Cardiac Cell;Developmental Biology;GPCR Dopamine D1like receptor;Metabolism;Regulation of insulin secretion;Phase 0 - rapid depolarisation;Phase 2 - plateau phase;Cardiac conduction;Muscle contraction;NCAM signaling for neurite out-growth;NCAM1 interactions;Axon guidance;Integration of energy metabolism
(Consensus)
Recessive Scores
- pRec
- 0.146
Intolerance Scores
- loftool
- 0.00420
- rvis_EVS
- -3.51
- rvis_percentile_EVS
- 0.32
Haploinsufficiency Scores
- pHI
- 0.540
- hipred
- Y
- hipred_score
- 0.693
- ghis
- 0.576
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.724
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Cacna1d
- Phenotype
- growth/size/body region phenotype; endocrine/exocrine gland phenotype; cellular phenotype; homeostasis/metabolism 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); hearing/vestibular/ear 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);
Zebrafish Information Network
- Gene name
- cacna1da
- Affected structure
- neuromast hair cell
- Phenotype tag
- abnormal
- Phenotype quality
- physical object quality
Gene ontology
- 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;positive regulation of calcium ion transport;regulation of atrial cardiac muscle cell membrane repolarization;calcium ion import;calcium ion transmembrane transport;cardiac muscle cell action potential involved in contraction;membrane depolarization during cardiac muscle cell action potential;membrane depolarization during SA node cell action potential;regulation of heart rate by cardiac conduction;induction of synaptic vesicle exocytosis by positive regulation of presynaptic cytosolic calcium ion concentration;regulation of potassium ion transmembrane transporter activity;regulation of potassium ion transmembrane transport
- Cellular component
- plasma membrane;voltage-gated calcium channel complex;Z disc;cochlear hair cell ribbon synapse;integral component of presynaptic active zone membrane;L-type voltage-gated calcium channel complex
- Molecular function
- voltage-gated calcium channel activity;calcium channel activity;high voltage-gated calcium channel activity;ankyrin binding;metal ion binding;alpha-actinin binding;voltage-gated calcium channel activity involved in cardiac muscle cell action potential;voltage-gated calcium channel activity involved SA node cell action potential;voltage-gated calcium channel activity involved in positive regulation of presynaptic cytosolic calcium levels