Human Gene Module / Chromosome 16 / CACNA1H

CACNA1Hcalcium channel, voltage-dependent, alpha 1H subunit

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 21
Rare Variants / Common Variants
22 / 0
Aliases
CACNA1H, T-type Ca(V)3.2 channels,  CACNA1HB
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
16p13.3
Associated Disorders
-
Relevance to Autism

Rare mutations in the CACNA1H gene have been identified with autism. In one study, missense mutations in CACNA1H were found in 6 of 461 individuals with ASD (Splawski et al., 2006).

Molecular Function

This gene encodes a T-type member of the alpha-1 subunit family, a protein in the voltage-dependent calcium channel complex. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization.

Reports related to CACNA1H (21 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy. Khosravani H , et al. (2004) No -
2 Primary CACNA1H mutations in autism spectrum disorders. Splawski I , et al. (2006) Yes -
3 Recent Recommendation Molecular characterization of T-type calcium channels. Perez-Reyes E (2006) No -
4 Recent Recommendation The I-II loop controls plasma membrane expression and gating of Ca(v)3.2 T-type Ca2 channels: a paradigm for childhood absence epilepsy mutations. Vitko I , et al. (2007) No -
5 Recent Recommendation Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants. Heron SE , et al. (2007) No -
6 Recent Recommendation CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells. Gackire F , et al. (2008) No -
7 Recent Recommendation Activation of corticotropin-releasing factor receptor 1 selectively inhibits CaV3.2 T-type calcium channels. Tao J , et al. (2008) No -
8 Recent Recommendation Transcriptional upregulation of Cav3.2 mediates epileptogenesis in the pilocarpine model of epilepsy. Becker AJ , et al. (2008) No -
9 Recent Recommendation Protein kinase A activity controls the regulation of T-type CaV3.2 channels by Gbetagamma dimers. Hu C , et al. (2009) No -
10 Recent Recommendation A Cav3.2 T-type calcium channel point mutation has splice-variant-specific effects on function and segregates with seizure expression in a polygeni... Powell KL , et al. (2009) No -
11 Recent Recommendation ACTH induces Cav3.2 current and mRNA by cAMP-dependent and cAMP-independent mechanisms. Liu H , et al. (2010) No -
12 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
13 Recent Recommendation A Ca(v)3.2/syntaxin-1A signaling complex controls T-type channel activity and low-threshold exocytosis. Weiss N , et al. (2011) No -
14 Recent Recommendation Transcriptional regulation of T-type calcium channel CaV3.2: bi-directionality by early growth response 1 (Egr1) and repressor element 1 (RE-1) pro... van Loo KM , et al. (2012) No -
15 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
16 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
17 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
18 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease. Karaca E , et al. (2015) No Microcephaly
19 Support Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms. D'Gama AM , et al. (2015) Yes -
20 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. Martnez F , et al. (2016) No -
21 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder. Takata A , et al. (2018) Yes -
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.634C>T p.Arg212Cys missense_variant Familial Maternal Multiplex 16754686 Splawski I , et al. (2006)
c.2704C>T p.Arg902Trp missense_variant Familial Maternal Simplex 16754686 Splawski I , et al. (2006)
- p.Trp962Cys missense_variant Unknown Not maternal Multiplex 16754686 Splawski I , et al. (2006)
c.[5612G>A];[5621C>T] p.[Arg1871Gln];[Ala1874Val] missense_variant Familial Paternal Multiplex 16754686 Splawski I , et al. (2006)
c.534C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.819C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2193G>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2841C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.5385G>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.6177C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2102C>T p.Pro701Leu missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2153A>G p.Glu718Gly missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2264G>A p.Gly755Asp missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2840C>T p.Thr947Ile missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4621A>G p.Ile1541Val missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.3008A>G p.Asn1003Ser missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.4913A>G p.His1638Arg missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
TATCATCA/TATCA - inframe_deletion De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.[2051C>A];[6898A>G] p.[Pro684His];[Ile2300Val] missense_variant;missense_variant Familial - Multiplex 26539891 Karaca E , et al. (2015)
c.5909C>G p.Ser1970Cys missense_variant Unknown - Unknown 26637798 D'Gama AM , et al. (2015)
c.2389C>T p.Arg797Cys missense_variant De novo - - 27620904 Martnez F , et al. (2016)
c.3565C>T p.Arg1189Cys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
Common Variants  

No common variants reported.

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.

10/1/2016
2
icon
2

Score remained at 2

Description

Rare variants seen to reduce Ca(V)3.2 channel activity present in 6 / 461 cases but none of 480 controls, imperfect segregation with disease as inherited from unaffected family members consistent with incomplete penetrance and/or polygenic etiology (Splawski I et al.); consistent with above, Heron et al. indicates that variants that are biologically functional and may predispose to seizures are insufficient to cause clinical features of disease (Heron, S. E. et al.).

1/1/2016
2
icon
2

Score remained at 2

Description

Rare variants seen to reduce Ca(V)3.2 channel activity present in 6 / 461 cases but none of 480 controls, imperfect segregation with disease as inherited from unaffected family members consistent with incomplete penetrance and/or polygenic etiology (Splawski I et al.); consistent with above, Heron et al. indicates that variants that are biologically functional and may predispose to seizures are insufficient to cause clinical features of disease (Heron, S. E. et al.).

Reports Added
[Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease.2015] [Extended spectrum of idiopathic generalized epilepsies associated with CACNA1H functional variants.2007] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [ACTH induces Cav3.2 current and mRNA by cAMP-dependent and cAMP-independent mechanisms.2010] [Gating effects of mutations in the Cav3.2 T-type calcium channel associated with childhood absence epilepsy.2004] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [CACNA1H mutations in autism spectrum disorders.2006] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [CaV3.2 T-type calcium channels are involved in calcium-dependent secretion of neuroendocrine prostate cancer cells.2008] [Transcriptional regulation of T-type calcium channel CaV3.2: bi-directionality by early growth response 1 (Egr1) and repressor element 1 (RE-1) pro...2012] [A Ca(v)3.2/syntaxin-1A signaling complex controls T-type channel activity and low-threshold exocytosis.2011] [Targeted DNA Sequencing from Autism Spectrum Disorder Brains Implicates Multiple Genetic Mechanisms.2015] [Molecular characterization of T-type calcium channels.2006] [The I-II loop controls plasma membrane expression and gating of Ca(v)3.2 T-type Ca2 channels: a paradigm for childhood absence epilepsy mutations.2007] [A Cav3.2 T-type calcium channel point mutation has splice-variant-specific effects on function and segregates with seizure expression in a polygeni...2009] [Protein kinase A activity controls the regulation of T-type CaV3.2 channels by Gbetagamma dimers.2009] [Activation of corticotropin-releasing factor receptor 1 selectively inhibits CaV3.2 T-type calcium channels.2008] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Transcriptional upregulation of Cav3.2 mediates epileptogenesis in the pilocarpine model of epilepsy.2008]
1/1/2015
2
icon
2

Score remained at 2

Description

Rare variants seen to reduce Ca(V)3.2 channel activity present in 6 / 461 cases but none of 480 controls, imperfect segregation with disease as inherited from unaffected family members consistent with incomplete penetrance and/or polygenic etiology (Splawski I et al.); consistent with above, Heron et al. indicates that variants that are biologically functional and may predispose to seizures are insufficient to cause clinical features of disease (Heron, S. E. et al.).

7/1/2014
No data
icon
2

Increased from No data to 2

Description

Rare variants seen to reduce Ca(V)3.2 channel activity present in 6 / 461 cases but none of 480 controls, imperfect segregation with disease as inherited from unaffected family members consistent with incomplete penetrance and/or polygenic etiology (Splawski I et al.); consistent with above, Heron et al. indicates that variants that are biologically functional and may predispose to seizures are insufficient to cause clinical features of disease (Heron, S. E. et al.).

4/1/2014
No data
icon
2

Increased from No data to 2

Description

Rare variants seen to reduce Ca(V)3.2 channel activity present in 6 / 461 cases but none of 480 controls, imperfect segregation with disease as inherited from unaffected family members consistent with incomplete penetrance and/or polygenic etiology (Splawski I et al.); consistent with above, Heron et al. indicates that variants that are biologically functional and may predispose to seizures are insufficient to cause clinical features of disease (Heron, S. E. et al.).

Krishnan Probability Score

Score 0.49392022083811

Ranking 3918/25841 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 0.75591697572235

Ranking 4175/18225 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
Iossifov Probability Score

Score 0.933

Ranking 104/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Sanders TADA Score

Score 0.76003783240927

Ranking 1659/18665 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 12

Ranking 155/461 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 0.11212218076864

Ranking 5876/20870 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 CACNA1H(1 CNVs)
16p13.3 45 Deletion-Duplication 70  /  465
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
CACNA1H calcium channel, voltage-dependent, T type, alpha 1H subunit Human Autoregulation 8912 O95180
Esr1 estrogen receptor 1 (alpha) Mouse DNA Binding 13982 P19785
Esr2 estrogen receptor 2 (beta) Mouse DNA Binding 13983 O08537
POMC proopiomelanocortin Human Direct Regulation 5443 P01189
PPP3R2 Calcineurin subunit B type 2 Human Protein Binding 5535 Q96LZ3
REST RE1-silencing transcription factor Human DNA Binding 5978 Q13127
USP5 ubiquitin specific peptidase 5 (isopeptidase T) Mouse Protein Binding 22225 P56399
WPP1 WW domain containing E3 ubiquitin protein ligase 1 Mouse Protein Binding 107568 Q8BZZ3
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