Human Gene Module / Chromosome 3 / CACNA2D3

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

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
10 / 13
Rare Variants / Common Variants
43 / 0
EAGLE Score
3.75
Limited Learn More
Aliases
CACNA2D3, HSA272268
Associated Syndromes
-
Chromosome Band
3p21.1-p14.3
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation, Functional
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).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CACNA2D3 (13 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 -
8 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
9 Support - Viggiano M et al. (2022) Yes -
10 Support - Bracic G et al. (2022) No -
11 Support - Santistevan NJ et al. (2022) No -
12 Support - Yuan B et al. (2023) Yes -
13 Support - Shao W et al. (2023) Yes -
Rare Variants   (43)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 27841880 Redin C , et al. (2016)
c.2987+1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.2987+1G>C - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.2830G>T p.Glu944Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1195C>T p.Arg399Ter stop_gained De novo - - 36881370 Yuan B et al. (2023)
c.427G>A p.Gly143Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.613C>T p.Arg205Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.812G>A p.Arg271His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.812G>T p.Arg271Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.917C>G p.Pro306Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.980T>C p.Leu327Pro missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1076G>A p.Ser359Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1993C>T p.Arg665Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2093C>T p.Ala698Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2167G>A p.Val723Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2167G>T p.Val723Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2195C>G p.Thr732Arg missense_variant De novo - - 33004838 Wang T et al. (2020)
c.2200C>T p.Leu734Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2318C>T p.Ala773Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2351C>T p.Ser784Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3125G>A p.Arg1042His missense_variant Unknown - - 33004838 Wang T et al. (2020)
A>T p.? splice_site_variant Familial - Multiplex 28263302 C Yuen RK et al. (2017)
c.613C>T p.Arg205Cys missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.2057-2A>G - splice_site_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2191C>G p.Arg731Gly missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.1522G>T p.Glu508Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1163G>A p.Arg388Gln missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.1259del p.Gln420ArgfsTer48 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
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.613C>G p.Arg205Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1018A>G p.Ile340Val missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.1360G>A p.Glu454Lys missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
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)
c.2164G>A p.Gly722Ser missense_variant Familial Paternal Simplex 33004838 Wang T et al. (2020)
C>T p.Thr965Ile missense_variant Familial Paternal Multiplex 35350424 Viggiano M et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2022
2
icon
1

Decreased from 2 to 1

10/1/2020
2
icon
2

Decreased from 2 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 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
1/1/2020
2
icon
2

Decreased from 2 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 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760).

Reports Added
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
10/1/2019
2
icon
2

Decreased from 2 to 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

Decreased from 2 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 < FDR 0.05, meaning that this gene had a 95% chance of being a true autism gene (PMID 25363760).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
4/1/2017
2
icon
2

Decreased from 2 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< FDR ?0.05, meaning that this gene had a ?95% chance of being a true autism gene (PMID 25363760).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
10/1/2016
2
icon
2

Decreased from 2 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

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.2016]
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.
Original Source
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
Original Source
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).
Original Source
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.
Original Source
Zhang D Score

Score 0.067563353594081

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.
Original Source
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