CACNA2D2

calcium voltage-gated channel auxiliary subunit alpha2delta 2, the group of Calcium voltage-gated channel auxiliary alpha2delta subunits

Basic information

Region (hg38): 3:50362613-50504244

Links

ENSG00000007402 ∙ NCBI:9254 ∙ OMIM:607082 ∙ HGNC:1400 ∙ Uniprot:Q9NY47 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cerebellar atrophy with seizures and variable developmental delay (Strong), mode of inheritance: AR
• cerebellar atrophy with seizures and variable developmental delay (Strong), mode of inheritance: AR
• complex neurodevelopmental disorder (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cerebellar atrophy with seizures and variable developmental delay	AR	General	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	Neurologic	23339110; 29997391
As with other conditions involving seizures, optimal seizure control is beneficial, and awareness of genetic causes may help with medication selection

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CACNA2D2 gene.

• Early infantile epileptic encephalopathy with suppression bursts (32 variants)
• Cerebellar atrophy with seizures and variable developmental delay (4 variants)
• not provided (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CACNA2D2 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			4	265	6	275
missense		1	380	5	3	389
nonsense	9	5	2			16
start loss						0
frameshift	27	1	2			30
inframe indel			7			7
splice donor/acceptor (+/-2bp)	2	15				17
splice region			38	82	2	122
non coding			11	200	32	243
Total	38	22	406	470	41

Highest pathogenic variant AF is 0.00000665

Variants in CACNA2D2

This is a list of pathogenic ClinVar variants found in the CACNA2D2 region.

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

Position	Type	Phenotype	Significance	ClinVar
3-50364667-C-T		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Jul 19, 2022)
3-50364667-CAGAGGCGGCG-C		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Oct 27, 2020)
3-50364672-GCGGCGAGAGGCGTGGAC-G		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Dec 27, 2019)
3-50364674-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Aug 15, 2022)
3-50364674-G-C		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (May 13, 2022)
3-50364675-G-T		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Jan 08, 2024)
3-50364681-G-A		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Oct 02, 2020)
3-50364684-G-A		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Jun 03, 2022)
3-50364690-G-A		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (May 20, 2022)
3-50364696-T-C		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (May 08, 2022)
3-50364696-T-G		Early infantile epileptic encephalopathy with suppression bursts • Inborn genetic diseases	Conflicting classifications of pathogenicity (Oct 17, 2022)
3-50364700-G-A		Cerebellar atrophy with seizures and variable developmental delay • Early infantile epileptic encephalopathy with suppression bursts • Inborn genetic diseases • CACNA2D2-related disorder	Benign/Likely benign (Jan 27, 2024)
3-50364701-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Jan 19, 2022)
3-50364705-C-T		Early infantile epileptic encephalopathy with suppression bursts • not specified	Benign (Jan 30, 2024)
3-50364706-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Mar 22, 2021)
3-50364708-C-CCGGGG		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Mar 19, 2022)
3-50364710-G-T		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Apr 03, 2018)
3-50364711-G-C		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Nov 25, 2023)
3-50364712-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (Aug 23, 2022)
3-50364714-C-T		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Dec 07, 2023)
3-50364717-C-T		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Jun 27, 2023)
3-50364720-G-A		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Feb 10, 2022)
3-50364725-G-A		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Apr 29, 2021)
3-50364726-G-A		Early infantile epileptic encephalopathy with suppression bursts	Likely benign (Apr 10, 2021)
3-50364728-G-A		Early infantile epileptic encephalopathy with suppression bursts	Uncertain significance (May 08, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CACNA2D2	protein_coding	protein_coding	ENST00000479441	39	141443

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.0000251	125725	0	18	125743	0.0000716

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.00	426	639	0.666	0.0000370	7495
Missense in Polyphen		134	269.56	0.49711		3042
Synonymous	-0.375	269	261	1.03	0.0000161	2208
Loss of Function	6.89	10	74.0	0.135	0.00000358	822

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000149	0.000149
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000798	0.0000791
Middle Eastern	0.00	0.00
South Asian	0.0000696	0.0000653
Other	0.000163	0.000163

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. Acts as a regulatory subunit for P/Q-type calcium channel (CACNA1A), N-type (CACNA1B), L-type (CACNA1C OR CACNA1D) and possibly T-type (CACNA1G). Overexpression induces apoptosis. {ECO:0000269|PubMed:12555074, ECO:0000269|PubMed:15111129}.
• 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;Levomethadyl Acetate Action Action Pathway;Disopyramide Action Pathway;Procainamide (Antiarrhythmic) Action Pathway;Phenytoin (Antiarrhythmic) Action Pathway;Fosphenytoin (Antiarrhythmic) Action Pathway;Bopindolol Action Pathway;Timolol Action Pathway;Carteolol Action Pathway;Fluoxetine Action Pathway;Citalopram Action Pathway;Escitalopram Action Pathway;Imipramine Action Pathway;Desipramine Action Pathway;Levallorphan Action Pathway;Dimethylthiambutene Action Pathway;Ethylmorphine Action Pathway;Pentazocine Action Pathway;Naltrexone Action Pathway;Buprenorphine Action Pathway;Alvimopan Action Pathway;Naloxone Action Pathway;Dihydromorphine Action Pathway;Bevantolol Action Pathway;Practolol Action Pathway;Glibenclamide Action Pathway;Gliclazide Action Pathway;Dobutamine Action Pathway;Isoprenaline Action Pathway;Arbutamine Action Pathway;Amiodarone Action Pathway;Levobunolol Action Pathway;Metipranolol Action Pathway;Mexiletine Action Pathway;Lidocaine (Antiarrhythmic) Action Pathway;Quinidine Action Pathway;Sotalol Action Pathway;Epinephrine Action Pathway;Betaxolol Action Pathway;Atenolol Action Pathway;Alprenolol Action Pathway;Acebutolol Action Pathway;Nicotine Action Pathway;Nalbuphine Action Pathway;Ketobemidone Action Pathway;Lidocaine (Local Anaesthetic) Action Pathway;Mepivacaine Action Pathway;Chloroprocaine Action Pathway;Cocaine Action Pathway;Dibucaine Action Pathway;Levobupivacaine Action Pathway;Benzocaine Action Pathway;Bupivacaine Action Pathway;Muscle/Heart Contraction;Diltiazem Action Pathway;Propranolol Action Pathway;Pindolol Action Pathway;Penbutolol Action Pathway;Oxprenolol Action Pathway;Metoprolol Action Pathway;Esmolol Action Pathway;Bisoprolol Action Pathway;Levorphanol Action Pathway;Propoxyphene Action Pathway;Tramadol Action Action Pathway;Bupranolol Action Pathway;Diphenoxylate Action Pathway;Anileridine Action Pathway;Methadone Action Pathway;Oxycodone Action Pathway;Oxybuprocaine Action Pathway;Prilocaine Action Pathway;Procaine Action Pathway;Proparacaine Action Pathway;Ropivacaine Action Pathway;Codeine Action Pathway;Morphine Action Pathway;Heroin Action Pathway;Nebivolol Action Pathway;Amlodipine Action Pathway;Verapamil Action Pathway;Nitrendipine Action Pathway;Nisoldipine Action Pathway;Nimodipine Action Pathway;Ibutilide Action Pathway;Tocainide Action Pathway;Flecainide Action Pathway;Pancreas Function;Alfentanil Action Pathway;Oxymorphone Action Pathway;Hydrocodone Action Pathway;Hydromorphone Action Pathway;Sufentanil Action Pathway;Remifentanil Action Pathway;Fentanyl Action Pathway;Carfentanil Action Pathway;Felodipine Metabolism Pathway;Isradipine Action Pathway;Nifedipine Action Pathway;Felodipine Action Pathway;Nadolol Action Pathway;Carvedilol Action Pathway;Labetalol Action Pathway;Repaglinide Action Pathway;Nateglinide Action Pathway;3-Methylthiofentanyl Action Pathway;Methadyl Acetate Action Pathway;Dezocine Action Pathway;Arrhythmogenic Right Ventricular Cardiomyopathy;MAPK Signaling Pathway;Metabolism;Regulation of insulin secretion;Neuronal System;Phase 0 - rapid depolarisation;Phase 2 - plateau phase;Cardiac conduction;Muscle contraction;Presynaptic depolarization and calcium channel opening;Transmission across Chemical Synapses;Integration of energy metabolism (Consensus)

Recessive Scores

• pRec: 0.154

Intolerance Scores

• loftool: 0.560
• rvis_EVS: -0.55
• rvis_percentile_EVS: 19.95

Haploinsufficiency Scores

• pHI: 0.489
• hipred: Y
• hipred_score: 0.623
• ghis: 0.433

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.184

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cacna2d2
• Phenotype: respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); reproductive system phenotype; normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); 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); hematopoietic 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); skeleton phenotype; homeostasis/metabolism phenotype; immune system phenotype; endocrine/exocrine gland phenotype; growth/size/body region phenotype; muscle phenotype

Gene ontology

• Biological process: neuromuscular junction development;regulation of ion transmembrane transport;regulation of multicellular organism growth;positive regulation of organ growth;muscle fiber development;regulation of insulin secretion;rhythmic synaptic transmission;calcium ion transmembrane transport
• Cellular component: plasma membrane;voltage-gated calcium channel complex
• Molecular function: voltage-gated calcium channel activity;metal ion binding