Human Gene Module / Chromosome 3 / CACNA2D3

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

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
15 / 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 (7 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 -
6 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model. Guo H , et al. (2018) Yes -
7 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo NA - 27841880 Redin C , et al. (2016)
A>T p.? splice_site_variant Familial - Multiplex 28263302 C Yuen RK et al. (2017)
c.2057-2A>G - splice_site_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.823G>A p.Ala275Thr missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.1398+1G>A - splice_site_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2318C>T p.Ala773Val missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.1522G>T p.Glu508Ter stop_gained De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.613C>G p.Arg205Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1993C>T p.Arg665Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1733G>A p.Arg578Gln missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.2092G>A p.Ala698Thr missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.2191C>G p.Arg731Gly missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.2266G>A p.Asp756Asn missense_variant Familial - Simplex 25363760 De Rubeis S , et al. (2014)
c.2093C>T p.Ala698Val missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2749G>A p.Ala917Thr missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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).

Score Delta: Score remained at 2

1

High Confidence

See all Category 1 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.

1/1/2020
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).

10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
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).

Reports Added
[New Scoring Scheme]
1/1/2019
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).

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.
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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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