GeneBe

CACNA2D1

protein-coding

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

Gene summary

The preproprotein encoded by this gene is cleaved into multiple chains that comprise the alpha-2 and delta subunits of the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. Mutations in this gene can cause cardiac deficiencies, including Brugada syndrome and short QT syndrome. Alternate splicing results in multiple transcript variants, some of which may lack the delta subunit portion. [provided by RefSeq, Nov 2014]

Previous symbols:
  • CACNL2A
  • CACNA2
  • MHS3
  • LINC01112

MANE transcript

NM_000722.4

Inheritance

AR, AD

ClinVar variants

P:5U:384B:317

Top phenotype

short QT syndrome

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr7:81,946,444-82,443,956

External References & Databases

Ensembl (ENSG00000153956)NCBI Gene (781)OMIM (114204)HGNC:1399GenCCUniProt (P54289)AlphaFoldClinVar (CACNA2D1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~497.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathy 110LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859327

Submitter: G2P

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: Ambry Genetics

developmental and epileptic encephalopathy 110LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859327

Submitter: Labcorp Genetics (formerly Invitae)

Brugada syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0015263

Submitter: G2P

Brugada syndrome 1NO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0011001

Submitter: ClinGen

Brugada syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0015263

Submitter: Genomics England PanelApp

short QT syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: ClinGen

CACNA2D1 encodes the alpha-2/delta-1 subunit of the calcium voltage-gated channel. A genetic variant in this gene was identified using a candidate-gene approach in a single case with cardiac arrest and a short QT interval (PMID 21383000). Other family members carrying this variant did not have a SQTS phenotype. Furthermore, this variant is now known to be present in >1% of Ashkenazi Jewish alleles, ruling it out as a monogenic cause of SQTS. In the absence of other genetic data, CACNA2D1 was classified as ‘Disputed’.

short QT syndromeNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: G2P

genetic developmental and epileptic encephalopathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100062

Submitter: Ambry Genetics

short QT syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000453

Submitter: Orphanet

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CACNA2D1 variants in ClinVar

10 Conditions Cataloged
Brugada syndromeTotal: 652
Cardiovascular phenotypeTotal: 548
not providedTotal: 147
not specifiedTotal: 65
CACNA2D1-related disorderTotal: 22
Developmental and epileptic encephalopathy 110Total: 8
Short QT syndromeTotal: 2
Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000722.4. 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.

EffectPLPVUSLBBSum
synonymous
6
clinvar
275
clinvar
1
clinvar
 282
missense
1
clinvar
357
clinvar
39
clinvar
1
clinvar
 398
nonsense
1
clinvar
5
clinvar
 6
start loss
0
frameshift
2
clinvar
4
clinvar
 6
splice donor/acceptor (+/-2bp)
1
clinvar
12
clinvar
1
clinvar
 14
Total323843152706

Highest pathogenic variant AF is 0.0000013683878

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000722.4RefSeqNP_000713.239MANE Select
ENST00000356860.8EnsemblENSP00000349320.339MANE Select
NM_001302890.2RefSeqNP_001289819.111Standard
NM_001366867.1RefSeqNP_001353796.139Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • 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)

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

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

Cellular Component

  • plasma membrane
  • voltage-gated calcium channel complex
  • sarcoplasmic reticulum
  • extracellular exosome
  • L-type voltage-gated calcium channel complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000356860
Coding exons
39
Length
497355
Individuals with no LoFs
125735
Homozygous LoFs
0
Heterozygous LoFs
13
Defined
125748
p
0.0000517
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.493365710.5890.00002847179
Missense (PolyPhen)822510.32673157
Synonymous1.081842040.9030.00001081936
Loss of Function6.811174.40.1480.00000378910

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish0.000100.000099rare
East Asian0.0000540.000054rare
Finnish0.0000460.000046rare
European (Non-Finnish)0.0000650.000062rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

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}.;

Intolerance Scores

LoFtool
0.258
RVIS EVS
-0.75
RVIS percentile EVS
13.58

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.163

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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