Human Gene Module / Chromosome 3 / CACNA1D

CACNA1Dcalcium channel, voltage-dependent, L type, alpha 1D

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 21
Rare Variants / Common Variants
47 / 1
Aliases
CACNA1D, CACH3,  CACN4,  CCHL1A2,  CACNL1A2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association, Functional
Chromosome Band
3p21.1
Associated Disorders
-
Relevance to Autism

Rare de novo missnese variants in the CACNA1D gene have been identified in ASD probands from the Simons Simplex Collection (ORoak et al., 2012; Iossifov et al., 2012).

Molecular Function

The encoded protein has low voltage-gated calcium channel activity. Mutations in this gene are responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474).

Reports related to CACNA1D (21 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Calcium channel activation and self-biting in mice. Jinnah HA , et al. (1999) No -
2 Highly Cited alpha 1D (Cav1.3) subunits can form l-type Ca2 channels activating at negative voltages. Koschak A , et al. (2001) No -
3 Support Association of CaV1.3 L-type calcium channels with Shank. Zhang H , et al. (2005) No -
4 Recent Recommendation Functional roles of Cav1.3(alpha1D) calcium channels in atria: insights gained from gene-targeted null mutant mice. Zhang Z , et al. (2005) No -
5 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
6 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
7 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
8 Support Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism. Scholl UI , et al. (2013) No -
9 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
10 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
11 Recent Recommendation CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels. Pinggera A , et al. (2015) No -
12 Support An autism-associated mutation in CaV1.3 channels has opposing effects on voltage- and Ca(2)-dependent regulation. Limpitikul WB , et al. (2016) No -
13 Support New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy. Pinggera A , et al. (2017) Yes -
14 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
15 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders. Li J , et al. (2017) Yes -
16 Support Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice. Tumien B , et al. (2017) No -
17 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection. Pardias AF , et al. (2018) No -
18 Support Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels. Pinggera A , et al. (2018) No -
19 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children. Long S , et al. (2019) Yes -
20 Support Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans. Wong WR , et al. (2019) Yes -
21 Support Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolesce... Jiao J , et al. (2019) Yes -
Rare Variants   (47)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
G>T - splice_site_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4262+560C>T - intron_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1534T>G p.Trp512Gly missense_variant De novo NA - 28714951 Lim ET , et al. (2017)
c.1493G>T p.Arg498Leu missense_variant Unknown - - 29286531 Tumien B , et al. (2017)
c.4444G>C p.Val1482Leu missense_variant De novo NA - 31139143 Long S , et al. (2019)
c.790A>G p.Ile264Val missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.920A>C p.Asp307Ala missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2206A>G p.Met736Val missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.4897C>T p.Gln1633Ter stop_gained Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1201G>C p.Val401Leu missense_variant De novo NA - 28472301 Pinggera A , et al. (2017)
c.3187C>T p.Arg1063Cys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.3862G>A p.Ala1288Thr missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.5846G>A p.Arg1949His missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.4232C>T p.Thr1411Met missense_variant De novo NA Simplex 31838722 Jiao J , et al. (2019)
c.1615G>C p.Ala539Pro missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1023C>T p.Asn341= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2802C>T p.Phe934= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.176C>T p.Ala59Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3952C>T p.Pro1318Ser missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.5381T>A p.Ile1794Asn missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.826C>T p.Leu276Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2306C>G p.Ala769Gly missense_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
c.1033A>C p.Thr345Pro missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1105G>A p.Val369Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1112A>C p.Tyr371Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1810G>A p.Val604Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2612T>G p.Leu871Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2789G>A p.Arg930His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1219G>A p.Gly407Arg missense_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.3578G>A p.Arg1193His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3788T>C p.Val1263Ala missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5023C>T p.Arg1675Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5990C>G p.Ser1997Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6053C>A p.Thr2018Asn missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6122G>A p.Arg2041His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6275G>A p.Gly2092Glu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1810G>A p.Val604Ile missense_variant De novo NA Simplex 25363760 De Rubeis S , et al. (2014)
c.1261G>A p.Asp421Asn missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1792G>A p.Gly598Ser missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2612T>G p.Leu871Trp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2612T>G p.Leu871Trp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2789G>A p.Arg930His missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3433C>G p.Arg1145Gly missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3607C>T p.Arg1203Cys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5816G>A p.Arg1939Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.6053C>A p.Thr2018Asn missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2015C>T p.Ser672Leu missense_variant De novo NA Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
G>A - intergenic_variant - - - 29483656 Pardias AF , et al. (2018)
SFARI Gene score
2

Strong Candidate

Two de novo missense variants in the CACNA1D gene were identified in ASD probands from the Simons Simplex Collection; neither of these variants were observed in controls or external databases (PMIDs 22495309, 22542183). Functional analysis of these variants following expression in tsA-201 cells and whole-cell patch-clamp studies showed that both variants caused significant changes in channel gating compatible with a gain-of-function phenotype (PMID 25620733). A third de novo missense variant that was shown experimentally to result in a gain-of-function phenotype was identified in a male patient presenting with ASD, intellectual disability, and epilepsy (PMID 28472301). Gain-of-function missense variants in this gene are also responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474) (PMID 23913001). Activation of L-type calcium channels in mice can induce self-biting behaviors (PMID 10611367), and CACNA1D has previously been shown to colocalize with Shank (PMID 15689539).

Score Delta: Score remained at 2

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.

1/1/2020
2
icon
2

Score remained at 2

Description

Two de novo missense variants in the CACNA1D gene were identified in ASD probands from the Simons Simplex Collection; neither of these variants were observed in controls or external databases (PMIDs 22495309, 22542183). Functional analysis of these variants following expression in tsA-201 cells and whole-cell patch-clamp studies showed that both variants caused significant changes in channel gating compatible with a gain-of-function phenotype (PMID 25620733). A third de novo missense variant that was shown experimentally to result in a gain-of-function phenotype was identified in a male patient presenting with ASD, intellectual disability, and epilepsy (PMID 28472301). Gain-of-function missense variants in this gene are also responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474) (PMID 23913001). Activation of L-type calcium channels in mice can induce self-biting behaviors (PMID 10611367), and CACNA1D has previously been shown to colocalize with Shank (PMID 15689539).

10/1/2019
2
icon
2

Score remained at 2

New Scoring Scheme
Description

Two de novo missense variants in the CACNA1D gene were identified in ASD probands from the Simons Simplex Collection; neither of these variants were observed in controls or external databases (PMIDs 22495309, 22542183). Functional analysis of these variants following expression in tsA-201 cells and whole-cell patch-clamp studies showed that both variants caused significant changes in channel gating compatible with a gain-of-function phenotype (PMID 25620733). A third de novo missense variant that was shown experimentally to result in a gain-of-function phenotype was identified in a male patient presenting with ASD, intellectual disability, and epilepsy (PMID 28472301). Gain-of-function missense variants in this gene are also responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474) (PMID 23913001). Activation of L-type calcium channels in mice can induce self-biting behaviors (PMID 10611367), and CACNA1D has previously been shown to colocalize with Shank (PMID 15689539).

Reports Added
[New Scoring Scheme]
7/1/2019
2
icon
2

Score remained at 2

Description

Two de novo missense variants in the CACNA1D gene were identified in ASD probands from the Simons Simplex Collection; neither of these variants were observed in controls or external databases (PMIDs 22495309, 22542183). Functional analysis of these variants following expression in tsA-201 cells and whole-cell patch-clamp studies showed that both variants caused significant changes in channel gating compatible with a gain-of-function phenotype (PMID 25620733). A third de novo missense variant that was shown experimentally to result in a gain-of-function phenotype was identified in a male patient presenting with ASD, intellectual disability, and epilepsy (PMID 28472301). Gain-of-function missense variants in this gene are also responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474) (PMID 23913001). Activation of L-type calcium channels in mice can induce self-biting behaviors (PMID 10611367), and CACNA1D has previously been shown to colocalize with Shank (PMID 15689539).

10/1/2018
2
icon
2

Score remained at 2

Description

Two de novo missense variants in the CACNA1D gene were identified in ASD probands from the Simons Simplex Collection; neither of these variants were observed in controls or external databases (PMIDs 22495309, 22542183). Functional analysis of these variants following expression in tsA-201 cells and whole-cell patch-clamp studies showed that both variants caused significant changes in channel gating compatible with a gain-of-function phenotype (PMID 25620733). A third de novo missense variant that was shown experimentally to result in a gain-of-function phenotype was identified in a male patient presenting with ASD, intellectual disability, and epilepsy (PMID 28472301). Gain-of-function missense variants in this gene are also responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474) (PMID 23913001). Activation of L-type calcium channels in mice can induce self-biting behaviors (PMID 10611367), and CACNA1D has previously been shown to colocalize with Shank (PMID 15689539).

10/1/2017
2
icon
2

Score remained at 2

Description

Two de novo missense variants in the CACNA1D gene were identified in ASD probands from the Simons Simplex Collection; neither of these variants were observed in controls or external databases (PMIDs 22495309, 22542183). Functional analysis of these variants following expression in tsA-201 cells and whole-cell patch-clamp studies showed that both variants caused significant changes in channel gating compatible with a gain-of-function phenotype (PMID 25620733). A third de novo missense variant that was shown experimentally to result in a gain-of-function phenotype was identified in a male patient presenting with ASD, intellectual disability, and epilepsy (PMID 28472301). Gain-of-function missense variants in this gene are also responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474) (PMID 23913001). Activation of L-type calcium channels in mice can induce self-biting behaviors (PMID 10611367), and CACNA1D has previously been shown to colocalize with Shank (PMID 15689539).

7/1/2017
2
icon
2

Score remained at 2

Description

Two de novo missense variants in the CACNA1D gene were identified in ASD probands from the Simons Simplex Collection; neither of these variants were observed in controls or external databases (PMIDs 22495309, 22542183). Functional analysis of these variants following expression in tsA-201 cells and whole-cell patch-clamp studies showed that both variants caused significant changes in channel gating compatible with a gain-of-function phenotype (PMID 25620733). A third de novo missense variant that was shown experimentally to result in a gain-of-function phenotype was identified in a male patient presenting with ASD, intellectual disability, and epilepsy (PMID 28472301). Gain-of-function missense variants in this gene are also responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474) (PMID 23913001). Activation of L-type calcium channels in mice can induce self-biting behaviors (PMID 10611367), and CACNA1D has previously been shown to colocalize with Shank (PMID 15689539).

4/1/2017
3
icon
2

Decreased from 3 to 2

Description

Two de novo missense variants in the CACNA1D gene were identified in ASD probands from the Simons Simplex Collection; neither of these variants were observed in controls or external databases (PMIDs 22495309, 22542183). Functional analysis of these variants following expression in tsA-201 cells and whole-cell patch-clamp studies showed that both variants caused significant changes in channel gating compatible with a gain-of-function phenotype (PMID 25620733). A third de novo missense variant that was shown experimentally to result in a gain-of-function phenotype was identified in a male patient presenting with ASD, intellectual disability, and epilepsy (PMID 28472301). Gain-of-function missense variants in this gene are also responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474) (PMID 23913001). Activation of L-type calcium channels in mice can induce self-biting behaviors (PMID 10611367), and CACNA1D has previously been shown to colocalize with Shank (PMID 15689539).

4/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo missense variants in the CACNA1D gene were identified in ASD probands from the Simons Simplex Collection; neither of these variants were observed in controls or external databases (PMIDs 22495309, 22542183). Functional analysis of these variants following expression in tsA-201 cells and whole-cell patch-clamp studies showed that both variants caused significant changes in channel gating compatible with a gain-of-function phenotype (PMID 25620733). Gain-of-function missense variants in this gene are also responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474) (PMID 23913001). Activation of L-type calcium channels in mice can induce self-biting behaviors, and CACNA1D has previously been shown to colocalize with Shank in mice (PMID 15689539).

1/1/2015
5
icon
3

Decreased from 5 to 3

Description

Two de novo missense variants in the CACNA1D gene were identified in ASD probands from the Simons Simplex Collection; neither of these variants were observed in controls or external databases (PMIDs 22495309, 22542183). Functional analysis of these variants following expression in tsA-201 cells and whole-cell patch-clamp studies showed that both variants caused significant changes in channel gating compatible with a gain-of-function phenotype (PMID 25620733). Gain-of-function missense variants in this gene are also responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474) (PMID 23913001). Activation of L-type calcium channels in mice can induce self-biting behaviors, and CACNA1D has previously been shown to colocalize with Shank in mice (PMID 15689539).

10/1/2014
5
icon
5

Decreased from 5 to 5

Description

CACNA1D is hypothesized BUT UNTESTED in autism due to the fact that activation of L-type calcium channels in mice can induce self-biting behaviors. In addition, CACNA1D has been show to colocalize with Shank in mice.

7/1/2014
No data
icon
5

Increased from No data to 5

Description

CACNA1D is hypothesized BUT UNTESTED in autism due to the fact that activation of L-type calcium channels in mice can induce self-biting behaviors. In addition, CACNA1D has been show to colocalize with Shank in mice.

4/1/2014
No data
icon
5

Increased from No data to 5

Description

CACNA1D is hypothesized BUT UNTESTED in autism due to the fact that activation of L-type calcium channels in mice can induce self-biting behaviors. In addition, CACNA1D has been show to colocalize with Shank in mice.

Krishnan Probability Score

Score 0.61096075086568

Ranking 210/25841 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 0.99999999998943

Ranking 51/18225 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 0.45513449587034

Ranking 361/18665 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 36

Ranking 58/461 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 0.46980064215933

Ranking 750/20870 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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