Human Gene Module / Chromosome 1 / CACNA1E

CACNA1Ecalcium voltage-gated channel subunit alpha1 E

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
5 / 12
Rare Variants / Common Variants
28 / 0
Aliases
CACNA1E, BII,  CACH6,  CACNL1A6,  Cav2.3
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
1q25.3
Associated Disorders
-
Relevance to Autism

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the CACNA1E gene in ASD probands (O'Roak et al., 2012; Neale et al., 2012). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.151E-02 (Takata et al., 2016).

Molecular Function

This gene encodes the alpha-1E subunit of R-type calcium channels, which belong to the 'high-voltage activated' group that may be involved in the modulation of firing patterns of neurons important for information processing.

Reports related to CACNA1E (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Altered cerebellar function in mice lacking CaV2.3 Ca2 channel. Osanai M , et al. (2006) No -
2 Support Cav2.3 channels are critical for oscillatory burst discharges in the reticular thalamus and absence epilepsy. Zaman T , et al. (2011) No -
3 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. O'Roak BJ , et al. (2012) Yes -
4 Support Patterns and rates of exonic de novo mutations in autism spectrum disorders. Neale BM , et al. (2012) Yes -
5 Support The CaV2.3 R-type voltage-gated Ca2 channel in mouse sleep architecture. Siwek ME , et al. (2014) 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 Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnose... Farwell Hagman KD , et al. (2016) No -
8 Support Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism. Chen R , et al. (2017) Yes -
9 Recent Recommendation De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias. Helbig KL , et al. (2018) No -
10 Support Impact of on-site clinical genetics consultations on diagnostic rate in children and young adults with autism spectrum disorder. Munnich A , et al. (2019) Yes -
11 Support De Novo Damaging DNA Coding Mutations Are Associated With Obsessive-Compulsive Disorder and Overlap With Tourette's Disorder and Autism. Cappi C , et al. (2019) No -
12 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. Satterstrom FK , et al. (2020) Yes -
Rare Variants   (28)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2485C>T p.Arg829Ter stop_gained Unknown - - 30343943 Helbig KL , et al. (2018)
c.4165C>T p.Arg1389Ter stop_gained Unknown - - 30343943 Helbig KL , et al. (2018)
c.683T>C p.Leu228Pro missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.1042G>C p.Gly348Arg missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.1054G>A p.Gly352Arg missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.1807A>C p.Ile603Leu missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.2069G>A p.Gly690Asp missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.2093T>C p.Phe698Ser missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.2098G>A p.Ala700Thr missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.2101A>G p.Ile701Val missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.2104G>A p.Ala702Thr missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.2104G>C p.Ala702Pro missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.4264A>T p.Ile1422Phe missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.4274C>A p.Thr1425Asn missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.4288G>A p.Gly1430Arg missense_variant De novo NA - 30343943 Helbig KL , et al. (2018)
c.3738C>T p.Asn1246%3D synonymous_variant De novo NA - 22495311 Neale BM , et al. (2012)
c.1375C>T p.Arg459Trp missense_variant De novo NA Simplex 28344757 Chen R , et al. (2017)
c.5258G>A p.Arg1753Gln missense_variant De novo NA Simplex 31771860 Cappi C , et al. (2019)
c.3625G>A p.Gly1209Ser missense_variant De novo NA Simplex 22495309 O'Roak BJ , et al. (2012)
c.4688A>G p.Lys1563Arg missense_variant De novo NA Simplex 31406558 Munnich A , et al. (2019)
c.5159C>G p.Ala1720Gly missense_variant Unknown Not maternal - 30343943 Helbig KL , et al. (2018)
c.934A>G p.Thr312Ala missense_variant De novo NA Simplex 31981491 Satterstrom FK , et al. (2020)
c.1375C>T p.Arg459Trp missense_variant De novo NA Simplex 31981491 Satterstrom FK , et al. (2020)
c.2555G>C p.Arg852Pro missense_variant De novo NA Simplex 31981491 Satterstrom FK , et al. (2020)
c.3422C>T p.Pro1141Leu missense_variant De novo NA Simplex 31981491 Satterstrom FK , et al. (2020)
c.2093T>C p.Phe698Ser missense_variant Unknown - Unknown 27513193 Farwell Hagman KD , et al. (2016)
c.2635C>T p.Arg879Trp missense_variant Unknown - Unknown 27513193 Farwell Hagman KD , et al. (2016)
c.4263_4271delinsG p.Ile1422HisfsTer8 frameshift_variant Familial Paternal - 30343943 Helbig KL , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the CACNA1E gene in ASD probands (O'Roak et al., 2012; Neale et al., 2012). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.151E-02 (Takata et al., 2016). Mice lacking the Ca(v)2.3 channel exhibited altered cerebellar function (Osanai et al., 2006). Lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to -butyrolactone-induced absence epilepsy in brain slices of Ca(v)2.3 knockout mice (Zaman et al., 2011). Ca(v)2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS) (Siwek et al., 2014). Helbig et al., 2018 described a developmental and epileptic encephalopathy with contractures, macrocephaly, and movement disorders associated with de novo missense variants in the CACNA1E gene; functional analysis of four of the missense variants observed in affected individuals (p.Phe698Ser, p.Ile701Val, p.Ala702Thr, and p.Ile603Leu) demonstrated gain-of-function effects.

Score Delta: Score remained at 3

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.

1/1/2020
3
icon
3

Score remained at 3

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the CACNA1E gene in ASD probands (O'Roak et al., 2012; Neale et al., 2012). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.151E-02 (Takata et al., 2016). Mice lacking the Ca(v)2.3 channel exhibited altered cerebellar function (Osanai et al., 2006). Lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to -butyrolactone-induced absence epilepsy in brain slices of Ca(v)2.3 knockout mice (Zaman et al., 2011). Ca(v)2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS) (Siwek et al., 2014). Helbig et al., 2018 described a developmental and epileptic encephalopathy with contractures, macrocephaly, and movement disorders associated with de novo missense variants in the CACNA1E gene; functional analysis of four of the missense variants observed in affected individuals (p.Phe698Ser, p.Ile701Val, p.Ala702Thr, and p.Ile603Leu) demonstrated gain-of-function effects.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the CACNA1E gene in ASD probands (O'Roak et al., 2012; Neale et al., 2012). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.151E-02 (Takata et al., 2016). Mice lacking the Ca(v)2.3 channel exhibited altered cerebellar function (Osanai et al., 2006). Lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to -butyrolactone-induced absence epilepsy in brain slices of Ca(v)2.3 knockout mice (Zaman et al., 2011). Ca(v)2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS) (Siwek et al., 2014). Helbig et al., 2018 described a developmental and epileptic encephalopathy with contractures, macrocephaly, and movement disorders associated with de novo missense variants in the CACNA1E gene; functional analysis of four of the missense variants observed in affected individuals (p.Phe698Ser, p.Ile701Val, p.Ala702Thr, and p.Ile603Leu) demonstrated gain-of-function effects.

Reports Added
[New Scoring Scheme]
7/1/2019
3
icon
3

Decreased from 3 to 3

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the CACNA1E gene in ASD probands (O'Roak et al., 2012; Neale et al., 2012). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.151E-02 (Takata et al., 2016). Mice lacking the Ca(v)2.3 channel exhibited altered cerebellar function (Osanai et al., 2006). Lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to -butyrolactone-induced absence epilepsy in brain slices of Ca(v)2.3 knockout mice (Zaman et al., 2011). Ca(v)2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS) (Siwek et al., 2014). Helbig et al., 2018 described a developmental and epileptic encephalopathy with contractures, macrocephaly, and movement disorders associated with de novo missense variants in the CACNA1E gene; functional analysis of four of the missense variants observed in affected individuals (p.Phe698Ser, p.Ile701Val, p.Ala702Thr, and p.Ile603Leu) demonstrated gain-of-function effects.

10/1/2018
3
icon
3

Decreased from 3 to 3

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the CACNA1E gene in ASD probands (O'Roak et al., 2012; Neale et al., 2012). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.151E-02 (Takata et al., 2016). Mice lacking the Ca(v)2.3 channel exhibited altered cerebellar function (Osanai et al., 2006). Lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to -butyrolactone-induced absence epilepsy in brain slices of Ca(v)2.3 knockout mice (Zaman et al., 2011). Ca(v)2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS) (Siwek et al., 2014). Helbig et al., 2018 described a developmental and epileptic encephalopathy with contractures, macrocephaly, and movement disorders associated with de novo missense variants in the CACNA1E gene; functional analysis of four of the missense variants observed in affected individuals (p.Phe698Ser, p.Ile701Val, p.Ala702Thr, and p.Ile603Leu) demonstrated gain-of-function effects.

7/1/2018
4.4 + acc
icon
3

Decreased from 4.4 + acc to 3

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the CACNA1E gene in ASD probands (O'Roak et al., 2012; Neale et al., 2012). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.151E-02 (Takata et al., 2016). Mice lacking the Ca(v)2.3 channel exhibited altered cerebellar function (Osanai et al., 2006). Lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to -butyrolactone-induced absence epilepsy in brain slices of Ca(v)2.3 knockout mice (Zaman et al., 2011). Ca(v)2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS) (Siwek et al., 2014).

4/1/2018
3
icon
4.4 + acc

Increased from 3 to 4.4 + acc

Description

3

4/1/2017
3
icon
3

Increased from 3 to 3

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the CACNA1E gene in ASD probands (O'Roak et al., 2012; Neale et al., 2012). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.151E-02 (Takata et al., 2016). Mice lacking the Ca(v)2.3 channel exhibited altered cerebellar function (Osanai et al., 2006). Lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to ?-butyrolactone-induced absence epilepsy in brain slices of Ca(v)2.3 knockout mice (Zaman et al., 2011). Ca(v)2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS) (Siwek et al., 2014).

7/1/2016
3
icon
3

Increased from 3 to 3

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the CACNA1E gene in ASD probands (O'Roak et al., 2012; Neale et al., 2012). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.151E-02 (Takata et al., 2016). Mice lacking the Ca(v)2.3 channel exhibited altered cerebellar function (Osanai et al., 2006). Lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to ?-butyrolactone-induced absence epilepsy in brain slices of Ca(v)2.3 knockout mice (Zaman et al., 2011). Ca(v)2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS) (Siwek et al., 2014).

4/1/2016
icon
3

Increased from to 3

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the CACNA1E gene in ASD probands (O'Roak et al., 2012; Neale et al., 2012). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.151E-02 (Takata et al., 2016). Mice lacking the Ca(v)2.3 channel exhibited altered cerebellar function (Osanai et al., 2006). Lack of Ca(v)2.3 resulted in a marked decrease in the sensitivity of the animal to ?-butyrolactone-induced absence epilepsy in brain slices of Ca(v)2.3 knockout mice (Zaman et al., 2011). Ca(v)2.3 deficient mice exhibited reduced wake duration and increased slow-wave sleep (SWS) (Siwek et al., 2014).

Krishnan Probability Score

Score 0.597047103121

Ranking 432/25841 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 0.99999999999993

Ranking 25/18225 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 0.943

Ranking 94/239 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 0.94096006178293

Ranking 14757/18665 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 -0.15782588709529

Ranking 14361/20870 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
MET met proto-oncogene Mouse Protein Binding 17295 P16056
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