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 p.? 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

2

Score Delta: Score remained at 2.1

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.

4/1/2017
2
icon
2

Score remained at 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).

10/1/2016
2
icon
2

Score remained at 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

10/1/2014
icon
2

Increased from to 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

Krishnan Probability Score

Score 0.49846198332908

Ranking 2243/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
ExAC Score

Score 0.99803225514561

Ranking 1251/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Sanders TADA Score

Score 0.12225209535308

Ranking 74/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Larsen Cumulative Evidence Score

Score 24

Ranking 81/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score 0.06756335359408

Ranking 6810/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
CNVs associated with CACNA2D3(1 CNVs)
3p21.1-p14.3 2 Deletion 3  /  2
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