CACNA2D1

calcium voltage-gated channel auxiliary subunit alpha2delta 1, the group of Calcium voltage-gated channel auxiliary alpha2delta subunits

Basic information

Region (hg38): 7:81946444-82443956

Previous symbols: [ "CACNL2A", "CACNA2", "MHS3", "LINC01112" ]

Links

ENSG00000153956 ∙ NCBI:781 ∙ OMIM:114204 ∙ HGNC:1399 ∙ Uniprot:P54289 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Brugada syndrome (Limited), mode of inheritance: Unknown
• short QT syndrome (Supportive), mode of inheritance: AD
• developmental and epileptic encephalopathy (Limited), mode of inheritance: AD
• Brugada syndrome (Disputed Evidence), mode of inheritance: AD
• developmental and epileptic encephalopathy 110 (Limited), mode of inheritance: AR
• Brugada syndrome 1 (Disputed Evidence), mode of inheritance: AD
• short QT syndrome (Disputed Evidence), mode of inheritance: AD

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CACNA2D1 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CACNA2D1 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			6	173	4	183
missense			242	11	2	255
nonsense			4			4
start loss						0
frameshift			2			2
inframe indel			3			3
splice donor/acceptor (+/-2bp)			2	1		3
splice region			23	54	9	86
non coding			5	182	104	291
Total	0	0	264	367	110

Variants in CACNA2D1

This is a list of pathogenic ClinVar variants found in the CACNA2D1 region.

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

Position	Type	Phenotype	Significance	ClinVar
7-81950198-C-A			Likely benign (Jul 15, 2018)
7-81950272-A-T			Benign (Jul 06, 2018)
7-81950393-C-T		Brugada syndrome	Likely benign (Feb 25, 2023)
7-81950394-A-G		Cardiovascular phenotype • Brugada syndrome	Uncertain significance (Jan 31, 2024)
7-81950398-C-T		Cardiovascular phenotype	Likely benign (Feb 24, 2017)
7-81950402-C-A		Brugada syndrome • Cardiovascular phenotype	Uncertain significance (May 11, 2023)
7-81950402-C-T		Brugada syndrome • Cardiovascular phenotype	Uncertain significance (Sep 08, 2023)
7-81950403-G-A		Cardiovascular phenotype • Brugada syndrome	Likely benign (Oct 17, 2023)
7-81950408-G-A		Brugada syndrome • Cardiovascular phenotype	Uncertain significance (Oct 19, 2023)
7-81950414-C-T		Cardiovascular phenotype • Brugada syndrome	Uncertain significance (Jan 01, 2023)
7-81950415-C-T		Cardiovascular phenotype	Uncertain significance (Sep 06, 2023)
7-81950416-A-G		Cardiovascular phenotype	Likely benign (Jun 18, 2021)
7-81950419-T-C		Cardiovascular phenotype	Likely benign (Mar 16, 2020)
7-81950426-C-A		Brugada syndrome	Uncertain significance (Jun 27, 2023)
7-81950433-G-C		Cardiovascular phenotype	Uncertain significance (Oct 14, 2016)
7-81950450-A-G		Cardiovascular phenotype • Brugada syndrome	Uncertain significance (Nov 07, 2023)
7-81950456-T-G		Brugada syndrome	Uncertain significance (Nov 20, 2023)
7-81950457-A-G		Brugada syndrome • Cardiovascular phenotype	Uncertain significance (Apr 29, 2021)
7-81950460-A-G		Brugada syndrome	Uncertain significance (Jul 13, 2021)
7-81950467-G-A		Cardiovascular phenotype • Brugada syndrome	Likely benign (Mar 16, 2023)
7-81950467-G-C		Cardiovascular phenotype	Likely benign (Apr 06, 2022)
7-81950483-A-C		Cardiovascular phenotype	Uncertain significance (Nov 24, 2021)
7-81950491-A-ACAGT		Brugada syndrome	Uncertain significance (Nov 24, 2023)
7-81950498-G-C		Brugada syndrome • Cardiovascular phenotype	Uncertain significance (Oct 23, 2021)
7-81950501-T-A		Brugada syndrome	Uncertain significance (Jun 27, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CACNA2D1	protein_coding	protein_coding	ENST00000356860	39	497355

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.000109	125735	0	13	125748	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.49	336	571	0.589	0.0000284	7179
Missense in Polyphen		82	251	0.3267		3157
Synonymous	1.08	184	204	0.903	0.0000108	1936
Loss of Function	6.81	11	74.4	0.148	0.00000378	910

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000585	0.0000585
Ashkenazi Jewish	0.0000998	0.0000992
East Asian	0.0000545	0.0000544
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000651	0.0000615
Middle Eastern	0.0000545	0.0000544
South Asian	0.0000334	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. Plays an important role in excitation-contraction coupling (By similarity). {ECO:0000250}.
• Pathway: Oxytocin signaling pathway - Homo sapiens (human);Cardiac muscle contraction - Homo sapiens (human);Dilated cardiomyopathy (DCM) - Homo sapiens (human);Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Hypertrophic cardiomyopathy (HCM) - Homo sapiens (human);Adrenergic signaling in cardiomyocytes - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Celecoxib Pathway, Pharmacodynamics;miR-targeted genes in lymphocytes - TarBase;miR-targeted genes in muscle cell - TarBase;Arrhythmogenic Right Ventricular Cardiomyopathy;MAPK Signaling Pathway;GPCR Dopamine D1like receptor;Neuronal System;Phase 0 - rapid depolarisation;Phase 2 - plateau phase;Cardiac conduction;Muscle contraction;Presynaptic depolarization and calcium channel opening;Transmission across Chemical Synapses (Consensus)

Intolerance Scores

• loftool: 0.258
• rvis_EVS: -0.75
• rvis_percentile_EVS: 13.58

Haploinsufficiency Scores

• pHI: 0.363
• hipred: Y
• hipred_score: 0.753
• ghis: 0.547

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.163

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Cacna2d1
• Phenotype: renal/urinary system 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); 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); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); muscle phenotype

Gene ontology

• Biological process: calcium ion transport;regulation of calcium ion transport;regulation of ventricular cardiac muscle cell membrane repolarization;calcium ion transport into cytosol;calcium ion transmembrane transport via high voltage-gated calcium channel;cardiac muscle cell action potential involved in contraction;membrane depolarization during bundle of His cell action potential;regulation of heart rate by cardiac conduction;calcium ion import across plasma membrane;regulation of membrane repolarization during action potential;positive regulation of high voltage-gated calcium channel activity;regulation of calcium ion transmembrane transport via high voltage-gated calcium channel;cellular response to amyloid-beta
• Cellular component: plasma membrane;voltage-gated calcium channel complex;sarcoplasmic reticulum;extracellular exosome;L-type voltage-gated calcium channel complex
• Molecular function: voltage-gated calcium channel activity;metal ion binding;voltage-gated calcium channel activity involved in cardiac muscle cell action potential;voltage-gated calcium channel activity involved in bundle of His cell action potential