Human Gene Module / Chromosome 17 / CACNA1G

CACNA1Gcalcium channel, voltage-dependent, T type, alpha 1G subunit

Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 20
Rare Variants / Common Variants
27 / 8
Aliases
CACNA1G, NBR13,  Cav3.1,  Ca(V)T.1,  MGC117234
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
17q21.33
Associated Disorders
DD/NDD, EPS, ID, ASD
Relevance to Autism

Genetic association has been found between the CACNA1G gene and autism in the AGRE cohort (Strom et al., 2010). Recently, a de novo synonymous variant in this gene was identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2012).

Molecular Function

Voltage-activated calcium channels

Reports related to CACNA1G (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Inactivation of CACNA1G, a T-type calcium channel gene, by aberrant methylation of its 5' CpG island in human tumors. Toyota M , et al. (1999) No -
2 Highly Cited Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2) channels. Kim D , et al. (2001) No -
3 Highly Cited T-type calcium channel regulation by specific G-protein betagamma subunits. Wolfe JT , et al. (2003) No -
4 Recent Recommendation 17Beta-estradiol regulation of the mRNA expression of T-type calcium channel subunits: role of estrogen receptor alpha and estrogen receptor beta. Bosch MA , et al. (2008) No -
5 Recent Recommendation Genetic enhancement of thalamocortical network activity by elevating alpha 1g-mediated low-voltage-activated calcium current induces pure absence e... Ernst WL , et al. (2009) No -
6 Primary High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene. Strom SP , et al. (2009) Yes -
7 Recent Recommendation Three-dimensional structure of CaV3.1: comparison with the cardiac L-type voltage-gated calcium channel monomer architecture. Walsh CP , et al. (2009) No -
8 Recent Recommendation Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive. Park YG , et al. (2010) No -
9 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy. Klassen T , et al. (2011) No -
10 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
11 Support Support for calcium channel gene defects in autism spectrum disorders. Lu AT , et al. (2012) Yes -
12 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
13 Support Large-scale discovery of novel genetic causes of developmental disorders. Deciphering Developmental Disorders Study (2014) No -
14 Support Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families. Alazami AM , et al. (2015) No -
15 Recent Recommendation A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia. Coutelier M , et al. (2015) No -
16 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Takata A , et al. (2016) No -
17 Recent Recommendation Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a. Calhoun JD , et al. (2016) No -
18 Positive Association Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ... Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017) Yes -
19 Support De novo mutation screening in childhood-onset cerebellar atrophy identifies gain-of-function mutations in the CACNA1G calcium channel gene. Chemin J , et al. (2018) No DD, ID, epilepsy/seizures, autistic behavior
20 Support Increased diagnostic and new genes identification outcome using research reanalysis of singleton exome sequencing. Bruel AL , et al. (2019) No -
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
T>A - splice_site_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
C>T - 2KB_upstream_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2881G>A p.Ala961Thr missense_variant De novo - - 29878067 Chemin J , et al. (2018)
c.4591A>G p.Met1531Val missense_variant De novo - - 29878067 Chemin J , et al. (2018)
c.4591A>G p.Met1531Val missense_variant De novo - - 31231135 Bruel AL , et al. (2019)
c.153G>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.546C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.915C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1464C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1770T>C p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1917G>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4084C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4956C>T p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.6156G>A p.(=) synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.561G>A p.(=) synonymous_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.561G>A p.(=) synonymous_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.72C>G p.Asp24Glu missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.286G>A p.Val96Met missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1345C>T p.Arg449Cys missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.1556C>T p.Pro519Leu missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4780C>T p.His1594Tyr missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.6130C>T p.Pro2044Ser missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.6542C>A p.Pro2181His missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4142G>A p.Arg1381Gln missense_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.3599A>G p.Asn1200Ser missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.5144G>A p.Arg1715His missense_variant Familial Maternal and paternal Multi-generational 26456284 Coutelier M , et al. (2015)
c.[667_669del];[667_669del] p.[Phe223del];[Phe223del] inframe_deletion;inframe_deletion Familial Both parents Multiplex 25558065 Alazami AM , et al. (2015)
Common Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.243-2430T>C - intron_variant - - - 28540026 Autism Spectrum Disorders Working Group of The Psychiatric Genomics Consortium (2017)
c.243-620G>T T/G intron_variant - - - 23241247 Lu AT , et al. (2012)
c.243-3538C>T T/C intron_variant - - - 23241247 Lu AT , et al. (2012)
c.489-56T>G G/T intron_variant - - - 19455149 Strom SP , et al. (2009)
c.1141-29A>G;c.1141-80A>G A to G intron_variant - - - 19455149 Strom SP , et al. (2009)
c.2302-1483A>G;c.2251-1483A>G G/A intron_variant - - - 19455149 Strom SP , et al. (2009)
c.2301+3918A>G;c.2250+3918A>G A to G intron_variant - - - 19455149 Strom SP , et al. (2009)
c.2302-3203C>T;c.2251-3203C>T T to C intron_variant - - - 19455149 Strom SP , et al. (2009)
SFARI Gene score
3

Suggestive Evidence

Located in a linkage region with association not explaining linkage. Genetic association has been found between the CACNA1G gene and autism in the AGRE cohort (PMID 19455149) and a cohort using families from AGRE and AGP (PMID 23241247). Recently, a de novo synonymous variant in this gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). A homozygous in-frame deletion variant in the CACNA1G gene segregated with disease in a consanguineous multiplex family affected by severe intellectual disability (PMID 25558065).

Score Delta: Score remained at 4

3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

7/1/2019
4
icon
4

Score remained at 4

Description

Located in a linkage region with association not explaining linkage. Genetic association has been found between the CACNA1G gene and autism in the AGRE cohort (PMID 19455149) and a cohort using families from AGRE and AGP (PMID 23241247). Recently, a de novo synonymous variant in this gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). A homozygous in-frame deletion variant in the CACNA1G gene segregated with disease in a consanguineous multiplex family affected by severe intellectual disability (PMID 25558065).

7/1/2018
4.3
icon
4

Score remained at 4

Description

Located in a linkage region with association not explaining linkage. Genetic association has been found between the CACNA1G gene and autism in the AGRE cohort (PMID 19455149) and a cohort using families from AGRE and AGP (PMID 23241247). Recently, a de novo synonymous variant in this gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). A homozygous in-frame deletion variant in the CACNA1G gene segregated with disease in a consanguineous multiplex family affected by severe intellectual disability (PMID 25558065).

4/1/2017
4
icon
4

Score remained at 4

Description

Located in a linkage region with association not explaining linkage. Genetic association has been found between the CACNA1G gene and autism in the AGRE cohort (PMID 19455149) and a cohort using families from AGRE and AGP (PMID 23241247). Recently, a de novo synonymous variant in this gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). A homozygous in-frame deletion variant in the CACNA1G gene segregated with disease in a consanguineous multiplex family affected by severe intellectual disability (PMID 25558065).

Reports Added
[High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene.2009] [De novo gene disruptions in children on the autistic spectrum.2012] [Support for calcium channel gene defects in autism spectrum disorders.2012] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Inactivation of CACNA1G, a T-type calcium channel gene, by aberrant methylation of its 5' CpG island in human tumors.1999] [Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2) channels.2001] [T-type calcium channel regulation by specific G-protein betagamma subunits.2003] [17Beta-estradiol regulation of the mRNA expression of T-type calcium channel subunits: role of estrogen receptor alpha and estrogen receptor beta.2008] [Genetic enhancement of thalamocortical network activity by elevating alpha 1g-mediated low-voltage-activated calcium current induces pure absence e...2009] [Three-dimensional structure of CaV3.1: comparison with the cardiac L-type voltage-gated calcium channel monomer architecture.2009] [Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive.2010] [A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.2015] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016] [Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a.2016] [Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with ...2017]
4/1/2016
4
icon
4

Score remained at 4

Description

Located in a linkage region with association not explaining linkage. Genetic association has been found between the CACNA1G gene and autism in the AGRE cohort (PMID 19455149) and a cohort using families from AGRE and AGP (PMID 23241247). Recently, a de novo synonymous variant in this gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). A homozygous in-frame deletion variant in the CACNA1G gene segregated with disease in a consanguineous multiplex family affected by severe intellectual disability (PMID 25558065).

Reports Added
[High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene.2009] [De novo gene disruptions in children on the autistic spectrum.2012] [Support for calcium channel gene defects in autism spectrum disorders.2012] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Inactivation of CACNA1G, a T-type calcium channel gene, by aberrant methylation of its 5' CpG island in human tumors.1999] [Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2) channels.2001] [T-type calcium channel regulation by specific G-protein betagamma subunits.2003] [17Beta-estradiol regulation of the mRNA expression of T-type calcium channel subunits: role of estrogen receptor alpha and estrogen receptor beta.2008] [Genetic enhancement of thalamocortical network activity by elevating alpha 1g-mediated low-voltage-activated calcium current induces pure absence e...2009] [Three-dimensional structure of CaV3.1: comparison with the cardiac L-type voltage-gated calcium channel monomer architecture.2009] [Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive.2010] [A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.2015] [The contribution of de novo coding mutations to autism spectrum disorder.2014] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016] [Cacna1g is a genetic modifier of epilepsy caused by mutation of voltage-gated sodium channel Scn2a.2016]
1/1/2016
4
icon
4

Score remained at 4

Description

Located in a linkage region with association not explaining linkage. Genetic association has been found between the CACNA1G gene and autism in the AGRE cohort (PMID 19455149) and a cohort using families from AGRE and AGP (PMID 23241247). Recently, a de novo synonymous variant in this gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). A homozygous in-frame deletion variant in the CACNA1G gene segregated with disease in a consanguineous multiplex family affected by severe intellectual disability (PMID 25558065).

Reports Added
[High-density SNP association study of the 17q21 chromosomal region linked to autism identifies CACNA1G as a novel candidate gene.2009] [De novo gene disruptions in children on the autistic spectrum.2012] [Support for calcium channel gene defects in autism spectrum disorders.2012] [Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.2011] [Accelerating novel candidate gene discovery in neurogenetic disorders via whole-exome sequencing of prescreened multiplex consanguineous families.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Inactivation of CACNA1G, a T-type calcium channel gene, by aberrant methylation of its 5' CpG island in human tumors.1999] [Lack of the burst firing of thalamocortical relay neurons and resistance to absence seizures in mice lacking alpha(1G) T-type Ca(2) channels.2001] [T-type calcium channel regulation by specific G-protein betagamma subunits.2003] [17Beta-estradiol regulation of the mRNA expression of T-type calcium channel subunits: role of estrogen receptor alpha and estrogen receptor beta.2008] [Genetic enhancement of thalamocortical network activity by elevating alpha 1g-mediated low-voltage-activated calcium current induces pure absence e...2009] [Three-dimensional structure of CaV3.1: comparison with the cardiac L-type voltage-gated calcium channel monomer architecture.2009] [Ca(V)3.1 is a tremor rhythm pacemaker in the inferior olive.2010] [A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia.2015] [The contribution of de novo coding mutations to autism spectrum disorder.2014]
7/1/2015
5
icon
4

Decreased from 5 to 4

Description

Located in a linkage region with association not explaining linkage. Genetic association has been found between the CACNA1G gene and autism in the AGRE cohort (PMID 19455149) and a cohort using families from AGRE and AGP (PMID 23241247). Recently, a de novo synonymous variant in this gene was identified in an ASD proband from the Simons Simplex Collection (PMID 22542183). A homozygous in-frame deletion variant in the CACNA1G gene segregated with disease in a consanguineous multiplex family affected by severe intellectual disability (PMID 25558065).

7/1/2014
No data
icon
5

Increased from No data to 5

Description

Located in a linkage region with association not explaining linkage.

4/1/2014
No data
icon
5

Increased from No data to 5

Description

Located in a linkage region with association not explaining linkage.

Krishnan Probability Score

Score 0.61300357141815

Ranking 149/25841 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 0.99999651736233

Ranking 377/18225 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 0.94010158668807

Ranking 14446/18665 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 13

Ranking 148/461 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 0.10146750835663

Ranking 6107/20870 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.
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Cacng6 calcium channel, voltage-dependent, gamma subunit 6 Rat Protein Binding 140727 Q8VHW7
KCND2 potassium voltage-gated channel, Shal-related subfamily, member 2 Human Protein Binding 3751 A4D0V9
LEF1 lymphoid enhancer-binding factor 1 Human DNA Binding 51176 Q659G9
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