Human Gene Module / Chromosome 7 / CACNA2D1

CACNA2D1calcium voltage-gated channel auxiliary subunit alpha2delta 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
11 / 0
Aliases
CACNA2D1, CACNA2,  CACNL2A,  CCHL2A,  LINC01112,  lncRNA-N3
Associated Syndromes
-
Chromosome Band
7q21.11
Associated Disorders
-
Relevance to Autism

A de novo missense variant that was predicted to be damaging (p.Arg351Thr) was observed in the CACNA2D1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); functional characterization of this variant in Risher et al., 2018 demonstrated that CACNA2D1-p.Arg351Thr failed to rescue defects in synaptogenesis in transfected organotypic slices from Cacna2d1-knockout mice. Genomic aberrations affecting the CACNA2D1 gene had previously been observed in three unrelated patients with intellectual disability and epilepsy (Vergult et al., 2015).

Molecular Function

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.

External Links
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Human
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SFARI Genomic Platforms
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Reports related to CACNA2D1 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Genomic aberrations of the CACNA2D1 gene in three patients with epilepsy and intellectual disability Vergult S , et al. (2014) No -
2 Primary The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Thrombospondin receptor ?2?-1 promotes synaptogenesis and spinogenesis via postsynaptic Rac1 Risher WC , et al. (2018) No -
4 Support - Rhine CL et al. (2022) Yes -
5 Support - Woodbury-Smith M et al. (2022) Yes -
6 Support - Dahimene S et al. (2022) No -
7 Support - Viggiano M et al. (2022) Yes -
8 Support - Zhou X et al. (2022) Yes -
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 25074461 Vergult S , et al. (2014)
- - translocation De novo - Simplex 25074461 Vergult S , et al. (2014)
- - copy_number_loss Familial Maternal Simplex 25074461 Vergult S , et al. (2014)
c.3101C>T p.Ala1034Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
C>G p.Asp820His missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.2903C>A p.Ser968Tyr missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.1052G>C p.Arg351Thr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.832del p.Glu278LysfsTer3 frameshift_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.626G>A p.Gly209Asp missense_variant Familial Paternal Simplex 35293990 Dahimene S et al. (2022)
c.818_821dupGAAC p.Ser275AsnfsTer13 frameshift_variant Familial Both parents - 35293990 Dahimene S et al. (2022)
c.13_23dupTGCCTGCTGGC p.Leu9AlafsTer5 frameshift_variant Familial Maternal Simplex 35293990 Dahimene S et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo missense variant that was predicted to be damaging (p.Arg351Thr) was observed in the CACNA2D1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); functional characterization of this variant in Risher et al., 2018 demonstrated that CACNA2D1-p.Arg351Thr failed to rescue defects in synaptogenesis in transfected organotypic slices from Cacna2d1-knockout mice. Genomic aberrations affecting the CACNA2D1 gene had previously been observed in three unrelated patients with intellectual disability and epilepsy (Vergult et al., 2015).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A de novo missense variant that was predicted to be damaging (p.Arg351Thr) was observed in the CACNA2D1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); functional characterization of this variant in Risher et al., 2018 demonstrated that CACNA2D1-p.Arg351Thr failed to rescue defects in synaptogenesis in transfected organotypic slices from Cacna2d1-knockout mice. Genomic aberrations affecting the CACNA2D1 gene had previously been observed in three unrelated patients with intellectual disability and epilepsy (Vergult et al., 2015).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo missense variant that was predicted to be damaging (p.Arg351Thr) was observed in the CACNA2D1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); functional characterization of this variant in Risher et al., 2018 demonstrated that CACNA2D1-p.Arg351Thr failed to rescue defects in synaptogenesis in transfected organotypic slices from Cacna2d1-knockout mice. Genomic aberrations affecting the CACNA2D1 gene had previously been observed in three unrelated patients with intellectual disability and epilepsy (Vergult et al., 2015).

Reports Added
[New Scoring Scheme]
7/1/2018
icon
4

Increased from to 4

Description

A de novo missense variant that was predicted to be damaging (p.Arg351Thr) was observed in the CACNA2D1 gene in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014); functional characterization of this variant in Risher et al., 2018 demonstrated that CACNA2D1-p.Arg351Thr failed to rescue defects in synaptogenesis in transfected organotypic slices from Cacna2d1-knockout mice. Genomic aberrations affecting the CACNA2D1 gene had previously been observed in three unrelated patients with intellectual disability and epilepsy (Vergult et al., 2015).

Krishnan Probability Score

Score 0.51050114320673

Ranking 1832/25841 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 0.99999580440422

Ranking 388/18225 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 0.90348715731473

Ranking 6743/18665 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
Zhang D Score

Score 0.47017502558419

Ranking 744/20870 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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