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
6 / 17
Rare Variants / Common Variants
45 / 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 (17 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 -
Rare Variants   (45)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1023C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2802C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1615G>C p.Ala539Pro missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
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>T - intron_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4897C>T p.Gln1633Ter stop_gained Unknown - Unknown 21703448 Klassen T , et al. (2011)
G>T - splice_site_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2306C>G p.Ala769Gly missense_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.1219G>A p.Gly407Arg missense_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.1810G>A p.Val604Ile missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.1261G>A p.Val421Ile missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1792G>A p.Ala598Thr missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1808G>A p.Arg603His missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4835G>A p.Arg1612Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5072C>A p.Thr1691Asn missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1631T>G p.Leu544Trp missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1631T>G p.Leu544Trp missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3373C>G p.Arg1125Gly missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3547C>T p.Arg1183Cys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.176C>T p.Ala59Val missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.52A>C p.Thr18Pro missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1631T>G p.Leu544Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1808G>A p.Arg603His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3518G>A p.Arg1173His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5009C>G p.Ser1670Leu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5072C>A p.Thr1691Asn missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5141G>A p.Arg1714His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.826C>T p.Leu276Phe 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.829G>A p.Val277Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3728T>C p.Val1243Ala missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4042C>T p.Arg1348Trp 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.6275G>A p.Gly2092Glu missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2015C>T p.Ser672Leu missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.1201G>C p.Val401Leu missense_variant De novo - - 28472301 Pinggera A , et al. (2017)
T>G p.Trp512Gly missense_variant De novo - - 28714951 Lim ET , et al. (2017)
c.2146A>G p.Met716Val missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.3127C>T p.Arg1043Cys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.3862G>A p.Glu1288Lys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.5714G>A p.Arg1905His missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
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.1493G>T p.Arg498Leu missense_variant Unknown - - 29286531 Tumien B , et al. (2017)
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

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.

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).

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.
CNVs associated with CACNA1D(1 CNVs)
3p21.1 7 Deletion 11  /  24
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