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

ENSG00000157388 ∙ NCBI:776 ∙ OMIM:114206 ∙ HGNC:1391 ∙ Uniprot:Q01668 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• 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: CGD

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 ClinVar and linked to the CACNA1D gene.

• not provided (4 variants)
• Aldosterone-producing adenoma with seizures and neurological abnormalities (1 variants)
• Sinoatrial node dysfunction and deafness (1 variants)
• Inborn genetic diseases (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.

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			10	416	10	436
missense	3	5	747	22	1	778
nonsense	1		14			15
start loss						0
frameshift			16			16
inframe indel	1		14	1		16
splice donor/acceptor (+/-2bp)		1	16			17
splice region			34	76		110
non coding			6	350	114	470
Total	5	6	823	789	125

Variants in CACNA1D

This is a list of pathogenic ClinVar variants found in the CACNA1D region.

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

Position	Type	Phenotype	Significance	ClinVar
3-53342263-G-T		not specified	Uncertain significance (Nov 01, 2022)
3-53344926-T-A		not specified	Uncertain significance (Feb 13, 2024)
3-53347453-T-C		not specified	Uncertain significance (Jul 25, 2023)
3-53347498-G-C		not specified	Uncertain significance (Nov 30, 2022)
3-53347510-G-A		not specified	Uncertain significance (Jul 27, 2021)
3-53494986-T-A			Benign (Nov 10, 2018)
3-53494986-T-TA			Likely benign (May 04, 2020)
3-53495113-T-C		Aldosterone-producing adenoma with seizures and neurological abnormalities • Sinoatrial node dysfunction and deafness	Benign (Jul 14, 2021)
3-53495165-GGAT-G			Uncertain significance (Jan 20, 2024)
3-53495165-GGATGATGAT-G			Uncertain significance (Mar 23, 2022)
3-53495165-GGATGATGATGAT-G			Uncertain significance (Jun 24, 2023)
3-53495165-G-GGAT		Inborn genetic diseases	Uncertain significance (Nov 08, 2023)
3-53495165-G-GGATGAT		Inborn genetic diseases	Uncertain significance (Jul 29, 2021)
3-53495171-T-C			Uncertain significance (Mar 20, 2022)
3-53495173-A-G			Uncertain significance (Jan 10, 2024)
3-53495187-GA-G			Uncertain significance (May 27, 2022)
3-53495188-A-G			Uncertain significance (Nov 25, 2022)
3-53495189-AA-TG			Uncertain significance (Jun 26, 2023)
3-53495202-T-C			Likely benign (Mar 22, 2023)
3-53495206-C-T			Uncertain significance (Jul 13, 2023)
3-53495207-G-A			Uncertain significance (Sep 29, 2021)
3-53495208-G-T			Uncertain significance (Dec 13, 2021)
3-53495213-A-G			Uncertain significance (Mar 08, 2022)
3-53495226-C-A			Uncertain significance (Dec 18, 2023)
3-53495227-G-A		Inborn genetic diseases	Uncertain significance (Jun 16, 2024)

GnomAD

Source: gnomAD

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: dbNSFP

• 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