Human Gene Module / Chromosome 22 / CACNA1I

CACNA1ICalcium channel, voltage-dependent, T type, alpha 1I subunit

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
8 / 11
Rare Variants / Common Variants
22 / 1
Aliases
CACNA1I, RP1-172B20.4,  Cav3.3,  ca(v)3.3
Associated Syndromes
-
Chromosome Band
22q13.1
Associated Disorders
-
Relevance to Autism

An imputed SNP within the CACNA1I gene (rs5750860) showed association with ASD in a family-based association study in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE) and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP) (Lu et al., 2012).

Molecular Function

This gene encodes the pore-forming alpha subunit of a voltage gated calcium channel. The encoded protein is a member of a subfamily of calcium channels referred to as is a low voltage-activated, T-type, calcium channel. The channel encoded by this protein is characterized by a slower activation and inactivation compared to other T-type calcium channels. This protein may be involved in calcium signaling in neurons.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CACNA1I (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Support for calcium channel gene defects in autism spectrum disorders Lu AT , et al. (2012) Yes -
2 Support Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network Gulsuner S , et al. (2013) No -
3 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
5 Support A rare schizophrenia risk variant of CACNA1I disrupts Ca V 3.3 channel activity Andrade A , et al. (2016) No -
6 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
7 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
8 Support - Wang C et al. (2022) No -
9 Support - Viggiano M et al. (2022) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Suhua Chang et al. () Yes -
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.5725+8G>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.164C>T p.Ala55Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.220A>G p.Lys74Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.707G>A p.Arg236His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.932A>G p.Asn311Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1478G>T p.Gly493Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1556C>G p.Pro519Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.4367G>T p.Arg1456Leu missense_variant Unknown - - 35220405 Wang C et al. (2022)
c.6247C>T p.His2083Tyr missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.6259G>C p.Glu2087Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1737C>A p.Ser579%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.4781G>A p.Arg1594Gln missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.5509G>A p.Gly1837Ser missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1416G>A p.Pro472= synonymous_variant De novo - Simplex 39126614 Suhua Chang et al. ()
c.4174G>A p.Val1392Met missense_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.4146C>T p.Ile1382= synonymous_variant De novo - Simplex 28714951 Lim ET , et al. (2017)
c.85C>T p.Arg29Trp missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.2390C>T p.Thr797Met missense_variant De novo - Simplex 23911319 Gulsuner S , et al. (2013)
c.3932G>A p.Arg1311His missense_variant De novo - Simplex 23911319 Gulsuner S , et al. (2013)
c.4575G>A p.Met1525Ile missense_variant Familial Paternal - 35350424 Viggiano M et al. (2022)
c.5318G>A p.Gly1773Asp missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.2817C>G p.Tyr939Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.581-4536C>T T/C intron_variant - - - 23241247 Lu AT , et al. (2012)
SFARI Gene score
2

Strong Candidate

An imputed SNP within the CACNA1I gene (rs5750860) showed association with ASD in a family-based association study in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE) and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP) with a P-value of 7.4E-06 (Lu et al., 2012). De novo missense variants in the CACNA1I gene that were predicted to be damaging were identified in two separate probands with schizophrenia (PMID 23911319).

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

An imputed SNP within the CACNA1I gene (rs5750860) showed association with ASD in a family-based association study in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE) and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP) with a P-value of 7.4E-06 (Lu et al., 2012). De novo missense variants in the CACNA1I gene that were predicted to be damaging were identified in two separate probands with schizophrenia (PMID 23911319).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

An imputed SNP within the CACNA1I gene (rs5750860) showed association with ASD in a family-based association study in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE) and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP) with a P-value of 7.4E-06 (Lu et al., 2012). De novo missense variants in the CACNA1I gene that were predicted to be damaging were identified in two separate probands with schizophrenia (PMID 23911319).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

An imputed SNP within the CACNA1I gene (rs5750860) showed association with ASD in a family-based association study in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE) and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP) with a P-value of 7.4E-06 (Lu et al., 2012). De novo missense variants in the CACNA1I gene that were predicted to be damaging were identified in two separate probands with schizophrenia (PMID 23911319).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2017
4
icon
4

Decreased from 4 to 4

Description

An imputed SNP within the CACNA1I gene (rs5750860) showed association with ASD in a family-based association study in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE) and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP) with a P-value of 7.4E-06 (Lu et al., 2012). De novo missense variants in the CACNA1I gene that were predicted to be damaging were identified in two separate probands with schizophrenia (PMID 23911319).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
10/1/2016
4
icon
4

Decreased from 4 to 4

Description

An imputed SNP within the CACNA1I gene (rs5750860) showed association with ASD in a family-based association study in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE) and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP) with a P-value of 7.4E-06 (Lu et al., 2012). De novo missense variants in the CACNA1I gene that were predicted to be damaging were identified in two separate probands with schizophrenia (PMID 23911319).

Reports Added
[A rare schizophrenia risk variant of CACNA1I disrupts CaV3.3 channel activity.2016]
1/1/2016
4
icon
4

Decreased from 4 to 4

Description

An imputed SNP within the CACNA1I gene (rs5750860) showed association with ASD in a family-based association study in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE) and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP) with a P-value of 7.4E-06 (Lu et al., 2012). De novo missense variants in the CACNA1I gene that were predicted to be damaging were identified in two separate probands with schizophrenia (PMID 23911319).

Reports Added
[Support for calcium channel gene defects in autism spectrum disorders.2012] [Spatial and temporal mapping of de novo mutations in schizophrenia to a fetal prefrontal cortical network.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
7/1/2015
icon
4

Increased from to 4

Description

An imputed SNP within the CACNA1I gene (rs5750860) showed association with ASD in a family-based association study in a combined sample of 2,781 parent/affected child trios from 543 multiplex Caucasian ASD families from the Autism Genetics Resource Exchange (AGRE) and 1,651 multiplex and simplex Caucasian ASD families from the Autism Genome Project (AGP) with a P-value of 7.4E-06 (Lu et al., 2012). De novo missense variants in the CACNA1I gene that were predicted to be damaging were identified in two separate probands with schizophrenia (PMID 23911319).

Krishnan Probability Score

Score 0.51227480245065

Ranking 1808/25841 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 0.9999988935132

Ranking 306/18225 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
Iossifov Probability Score

Score 0.883

Ranking 164/239 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
Original Source
Sanders TADA Score

Score 0.94516854831821

Ranking 16363/18665 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
Larsen Cumulative Evidence Score

Score 3

Ranking 331/461 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.
Original Source
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