Human Gene Module / Chromosome 19 / CACNA1A

CACNA1ACalcium channel, voltage-dependent, P/Q type, alpha 1A subunit

Score
S
Syndromic Syndromic
Autism Reports / Total Reports
5 / 17
Rare Variants / Common Variants
22 / 2
Aliases
CACNA1A, APCA,  BI,  CACNL1A4,  CAV2.1,  EA2,  FHM,  HPCA,  MHP,  MHP1,  SCA6
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Genetic Association
Chromosome Band
19p13.13
Associated Disorders
EPS, ID, DD/NDD, EP
Relevance to Autism

Variants affecting the CACNA1A gene were identified in affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual disability, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia (Damaj et al., 2015).

Molecular Function

This gene encodes the pore-forming alpha-1A subunit, which is predominantly expressed in neuronal tissue, for voltage-dependent calcium channels. Mutations in this gene are associated with several neurological disorders: episodic ataxia, type 2 (OMIM 108500); migraine, familial hemiplegic, 1 (OMIM 141500); and spinocerebellar atxia 6 (OMIM 183086).

Reports related to CACNA1A (17 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support CaV 2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures. Rossignol E , et al. (2013) No -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Primary CACNA1A haploinsufficiency causes cognitive impairment, autism and epileptic encephalopathy with mild cerebellar symptoms. Damaj L , et al. (2015) Yes Learning difficulties, ataxia
4 Negative Association Genetic Evidence for Possible Involvement of the Calcium Channel Gene CACNA1A in Autism Pathogenesis in Chinese Han Population. Li J , et al. (2015) Yes -
5 Recent Recommendation Isolated P/Q Calcium Channel Deletion in Layer VI Corticothalamic Neurons Generates Absence Epilepsy. Bomben VC , et al. (2016) No -
6 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Takata A , et al. (2016) No -
7 Support De Novo Mutations in SLC1A2 and CACNA1A Are Important Causes of Epileptic Encephalopathies. Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016) No -
8 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
9 Support Lessons learned from additional research analyses of unsolved clinical exome cases. Eldomery MK , et al. (2017) No Hypotonia, cerebellar atrophy
10 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Vissers LE , et al. (2017) No Oculomotor apraxia
11 Support High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Hamdan FF , et al. (2017) No DD/ID
12 Support Major intra-familial phenotypic heterogeneity and incomplete penetrance due to a CACNA1A pathogenic variant. Angelini C , et al. (2018) No ID, ataxia
13 Support The combination of whole-exome sequencing and copy number variation sequencing enables the diagnosis of rare neurological disorders. Jiao Q , et al. (2019) No ID
14 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes. Xiong J , et al. (2019) Yes Epilepsy/seizures
15 Support Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v... Lecoquierre F , et al. (2019) No -
16 Support The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children. Long S , et al. (2019) Yes -
17 Support The diagnostic yield of intellectual disability: combined whole genome low-coverage sequencing and medical exome sequencing Wang J et al. (2020) No -
Rare Variants   (22)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo NA - 31031587 Xiong J , et al. (2019)
c.4991G>A p.Arg1664Gln missense_variant De novo NA - 32429945 Wang J et al. (2020)
c.4046G>A p.Arg1349Gln missense_variant De novo NA - 31139143 Long S , et al. (2019)
c.4106T>G p.Val1369Gly missense_variant De novo NA - 28333917 Vissers LE , et al. (2017)
c.4082_4084del p.Lys1361del inframe_deletion De novo NA - 31139143 Long S , et al. (2019)
- - copy_number_loss Familial Maternal Multi-generational 25735478 Damaj L , et al. (2015)
c.5263G>A p.Glu1755Lys missense_variant De novo NA - 31036916 Lecoquierre F , et al. (2019)
c.2134G>A p.Ala712Thr missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.1173G>C p.Gly391= synonymous_variant De novo NA Simplex 25363768 Iossifov I et al. (2014)
c.4174G>A p.Val1392Met missense_variant De novo NA Simplex 29100083 Hamdan FF , et al. (2017)
c.5015G>C p.Arg1672Pro missense_variant De novo NA Simplex 28327206 Eldomery MK , et al. (2017)
NM_023035.3:c.7178G>A p.Gly2393Glu missense_variant Familial Maternal - 30945278 Jiao Q , et al. (2019)
c.835C>T p.Arg279Cys missense_variant Familial - Multi-generational 30142438 Angelini C , et al. (2018)
c.2040_2041del p.Gln681GlyfsTer103 frameshift_variant De novo NA - 27479843 Lelieveld SH et al. (2016)
c.3832C>T p.Arg1278Ter stop_gained Familial Paternal Multi-generational 25735478 Damaj L , et al. (2015)
c.873G>A p.Trp291Ter splice_site_variant Familial Maternal Multi-generational 25735478 Damaj L , et al. (2015)
c.2867_2869del p.Asp956del frameshift_variant Familial Maternal and paternal Multi-generational 25735478 Damaj L , et al. (2015)
c.653C>T p.Ser218Leu missense_variant Unknown - - 27476654 Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.301G>C p.Glu101Gln missense_variant De novo NA - 27476654 Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.2137G>A p.Ala713Thr missense_variant De novo NA - 27476654 Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.4531G>T p.Ala1511Ser missense_variant De novo NA - 27476654 Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
c.2137G>A p.Ala713Thr missense_variant Familial Maternal Multiplex 27476654 Epi4K Consortium. Electronic address: epi4k@columbia.edu and Epi4K Consortium (2016)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.293+17663A>C - intron_variant - - - 26566276 Li J , et al. (2015)
c.294-22490A>G - intron_variant - - - 26566276 Li J , et al. (2015)
SFARI Gene score
S

Syndromic

Variants affecting the CACNA1A gene were identified in affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual disability, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia (Damaj et al., 2015). Damaging missense and likely loss-of-functions in CACNA1A, many of which were de novo in origin, have subsequently been identified in individuals presenting with similar phenotypes (Epi4K Consortium 2016; Lelieveld et al., 2016; Eldomery et al., 2017; Vissers et al., 2017; Hamdan et al., 2017). A de novo synonymous variant in the CACNA1A gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was located near a splice-site and was predicted to affect splicing by altering the exonic splicing regulator (ESR) in Takata et al., 2016. SNPs in the CACNA1A gene associated with autism in a Chinese Han population in Li et al., 2015, although this association did not survive after Bonferroni correction. Mice carrying loss-of-function mutations in Cacna1a in a subset of cortical interneurons display severe generalized epilepsy (Rossignol et al., 2013).

Score Delta: Score remained at S

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2020
S
icon
S

Score remained at S

Description

Variants affecting the CACNA1A gene were identified in affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual disability, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia (Damaj et al., 2015). Damaging missense and likely loss-of-functions in CACNA1A, many of which were de novo in origin, have subsequently been identified in individuals presenting with similar phenotypes (Epi4K Consortium 2016; Lelieveld et al., 2016; Eldomery et al., 2017; Vissers et al., 2017; Hamdan et al., 2017). A de novo synonymous variant in the CACNA1A gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was located near a splice-site and was predicted to affect splicing by altering the exonic splicing regulator (ESR) in Takata et al., 2016. SNPs in the CACNA1A gene associated with autism in a Chinese Han population in Li et al., 2015, although this association did not survive after Bonferroni correction. Mice carrying loss-of-function mutations in Cacna1a in a subset of cortical interneurons display severe generalized epilepsy (Rossignol et al., 2013).

10/1/2019
S
icon
S

Score remained at S

New Scoring Scheme
Description

Variants affecting the CACNA1A gene were identified in affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual disability, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia (Damaj et al., 2015). Damaging missense and likely loss-of-functions in CACNA1A, many of which were de novo in origin, have subsequently been identified in individuals presenting with similar phenotypes (Epi4K Consortium 2016; Lelieveld et al., 2016; Eldomery et al., 2017; Vissers et al., 2017; Hamdan et al., 2017). A de novo synonymous variant in the CACNA1A gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was located near a splice-site and was predicted to affect splicing by altering the exonic splicing regulator (ESR) in Takata et al., 2016. SNPs in the CACNA1A gene associated with autism in a Chinese Han population in Li et al., 2015, although this association did not survive after Bonferroni correction. Mice carrying loss-of-function mutations in Cacna1a in a subset of cortical interneurons display severe generalized epilepsy (Rossignol et al., 2013).

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

Score remained at S

Description

Variants affecting the CACNA1A gene were identified in affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual disability, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia (Damaj et al., 2015). Damaging missense and likely loss-of-functions in CACNA1A, many of which were de novo in origin, have subsequently been identified in individuals presenting with similar phenotypes (Epi4K Consortium 2016; Lelieveld et al., 2016; Eldomery et al., 2017; Vissers et al., 2017; Hamdan et al., 2017). A de novo synonymous variant in the CACNA1A gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was located near a splice-site and was predicted to affect splicing by altering the exonic splicing regulator (ESR) in Takata et al., 2016. SNPs in the CACNA1A gene associated with autism in a Chinese Han population in Li et al., 2015, although this association did not survive after Bonferroni correction. Mice carrying loss-of-function mutations in Cacna1a in a subset of cortical interneurons display severe generalized epilepsy (Rossignol et al., 2013).

4/1/2019
S
icon
S

Score remained at S

Description

Variants affecting the CACNA1A gene were identified in affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual disability, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia (Damaj et al., 2015). Damaging missense and likely loss-of-functions in CACNA1A, many of which were de novo in origin, have subsequently been identified in individuals presenting with similar phenotypes (Epi4K Consortium 2016; Lelieveld et al., 2016; Eldomery et al., 2017; Vissers et al., 2017; Hamdan et al., 2017). A de novo synonymous variant in the CACNA1A gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was located near a splice-site and was predicted to affect splicing by altering the exonic splicing regulator (ESR) in Takata et al., 2016. SNPs in the CACNA1A gene associated with autism in a Chinese Han population in Li et al., 2015, although this association did not survive after Bonferroni correction. Mice carrying loss-of-function mutations in Cacna1a in a subset of cortical interneurons display severe generalized epilepsy (Rossignol et al., 2013).

10/1/2018
S
icon
S

Score remained at S

Description

Variants affecting the CACNA1A gene were identified in affected individuals from four unrelated families presenting with a spectrum of cognitive impairment including intellectual disability, executive dysfunction, ADHD and/or autism, as well as childhood-onset epileptic encephalopathy with refractory absence epilepsy, febrile seizures, downbeat nystagmus and episodic ataxia (Damaj et al., 2015). Damaging missense and likely loss-of-functions in CACNA1A, many of which were de novo in origin, have subsequently been identified in individuals presenting with similar phenotypes (Epi4K Consortium 2016; Lelieveld et al., 2016; Eldomery et al., 2017; Vissers et al., 2017; Hamdan et al., 2017). A de novo synonymous variant in the CACNA1A gene was identified in an ASD proband from the Simons Simplex Collection in Iossifov et al., 2014; this variant was located near a splice-site and was predicted to affect splicing by altering the exonic splicing regulator (ESR) in Takata et al., 2016. SNPs in the CACNA1A gene associated with autism in a Chinese Han population in Li et al., 2015, although this association did not survive after Bonferroni correction. Mice carrying loss-of-function mutations in Cacna1a in a subset of cortical interneurons display severe generalized epilepsy (Rossignol et al., 2013).

Krishnan Probability Score

Score 0.61038153156471

Ranking 231/25841 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 0.99999999977629

Ranking 80/18225 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 0.94806684873626

Ranking 17532/18665 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).
Zhang D Score

Score 0.41840424797678

Ranking 1256/20870 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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SFARI Gene Update

We are pleased to announce some changes to the ongoing curation of the data in SFARI Gene. In the context of a continued effort to develop the human gene module and its manually curated list of autism risk genes, we are modifying other aspects of the site to focus on the information that is of greatest interest to the research community. The version of SFARI Gene that has been developed until now will be frozen and will remain available as “SFARI Gene Archive”. Please see the announcement for more details.
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