Human Gene Module / Chromosome 19 / CACNA1A

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

Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
6 / 20
Rare Variants / Common Variants
26 / 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
DD/NDD, EPS, ASD, ID, 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 (20 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 Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants 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 -
18 Support - Rodin RE et al. (2021) Yes -
19 Support - Mojarad BA et al. (2021) No ID
20 Support - Liu L et al. (2021) No ASD
Rare Variants   (26)
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.118G>T p.Gly40Trp missense_variant De novo NA - 33432195 Rodin RE et al. (2021)
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.7205C>A p.Pro2402Gln missense_variant De novo NA Simplex 33951346 Liu L et al. (2021)
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.2042_2043del p.Gln681ArgfsTer103 frameshift_variant Unknown - Simplex 33526774 Mojarad BA et al. (2021)
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)
ENSG00000141837:ENST00000573710:exon19:c.A2504C:p.N835T,ENSG00000141837:ENST00000360228:exon19:c.A25 - missense_variant De novo NA - 33432195 Rodin RE et al. (2021)
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
1S

High Confidence, 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

1

High Confidence

See all Category 1 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.

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."

4/1/2021
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).

1/1/2021
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).

4/1/2020
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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