Human Gene Module / Chromosome 3 / CACNA2D3

CACNA2D3Calcium channel, voltage-dependent, alpha 2/delta subunit 3

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
13 / 0
Aliases
CACNA2D3, HSA272268
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
3p21.1-p14.3
Associated Disorders
-
Relevance to Autism

This gene was identified in an ASD whole-exome sequencing study and subsequent TADA (transmission and de novo association) analysis as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (De Rubeis et al., 2014).

Molecular Function

This gene encodes a member of the alpha-2/delta subunit family, a protein in the voltage-dependent calcium channel complex. 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) but not T-type (CACNA1G).

Reports related to CACNA2D3 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
2 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
3 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
4 Support The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies. Redin C , et al. (2016) No -
5 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2057-2A>G - splice_site_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.1522G>T p.Glu508Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1430G>A p.Arg477Gln missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.1810G>A p.Ala604Thr missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.1984G>A p.Asp662Asn missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.1909C>G p.Arg637Gly missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.1711C>T p.Arg571Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.328C>G p.Arg110Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2318C>T p.Ala773Val missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2318C>T p.Ala773Val missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.823G>A p.Ala275Thr missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
- - translocation De novo - - 27841880 Redin C , et al. (2016)
A>T p.? splice_site_variant Familial - Multiplex 28263302 C Yuen RK , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo LoF variant in the CACNA2D3 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183), while a second de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ADNP as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760).

2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

04-01-2017
2

Initial score established: 2

Description

A de novo LoF variant in the CACNA2D3 gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183), while a second de novo LoF variant in this gene was identified in one ASD proband from 2,270 trios screened by the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ADNP as a gene meeting high statistical significance with a 0.01< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760).

CNVs associated with CACNA2D3(1 CNVs)
3p21.1-p14.3 1 Deletion 2  /  1
Animal Models associated with CACNA2D3(2 Models)
CACNA2D3_1_KO_HM Genetic
CACNA2D3_1_KO_HT Genetic
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