Human Gene Module / Chromosome 9 / CACNA1B

CACNA1Bcalcium voltage-gated channel subunit alpha1 B

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 14
Rare Variants / Common Variants
34 / 0
Aliases
CACNA1B, BIII,  CACNL1A5,  CACNN,  Cav2.2
Associated Syndromes
Pediatric Acute-Onset Neuropsychiatric Syndrome (P
Chromosome Band
9q34.3
Associated Disorders
-
Relevance to Autism

In a study of 20 unrelated children with variable phenotypes found to have gains in DNA copy number in the subtelomeric 9q34 region, seven were found to carry monogenic duplications encompassing the CACNA1B gene. Four of these children with monogenic CACNA1B duplications were diagnosed with ASD (Yatensko et al., 2012).

Molecular Function

The protein encoded by this gene is the pore-forming subunit of an N-type voltage-dependent calcium channel, which controls neurotransmitter release from neurons. The encoded protein forms a complex with alpha-2, beta, and delta subunits to form the high-voltage activated channel. This channel is sensitive to omega-conotoxin-GVIA and omega-agatoxin-IIIA but insensitive to dihydropyridines.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CACNA1B (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association Gene-wide analyses of genome-wide association data sets: evidence for multiple common risk alleles for schizophrenia and bipolar disorder and for overlap in genetic risk Moskvina V , et al. (2008) No -
2 Positive Association Strong synaptic transmission impact by copy number variations in schizophrenia Glessner JT , et al. (2010) No -
3 Support Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy Klassen T , et al. (2011) No -
4 Primary Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage-fusion-bridge for telomere stabilization Yatsenko SA , et al. (2012) Yes -
5 Support A discovery resource of rare copy number variations in individuals with autism spectrum disorder Prasad A , et al. (2013) Yes -
6 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
7 Support Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder Krupp DR , et al. (2017) Yes -
8 Support Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia Gorman KM , et al. (2019) No Developmental regression, microcephaly, hypotonia
9 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
10 Support - Viggiano M et al. (2022) Yes -
11 Support - Teles E Silva AL et al. (2022) Yes -
12 Support - Trifiletti R et al. (2022) No -
13 Support - Zhou X et al. (2022) Yes -
14 Support - Omri Bar et al. (2024) Yes ID
Rare Variants   (34)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain De novo - - 22890305 Yatsenko SA , et al. (2012)
- - copy_number_gain Unknown - - 22890305 Yatsenko SA , et al. (2012)
- - copy_number_gain Unknown - Unknown 23275889 Prasad A , et al. (2013)
- - copy_number_gain Familial Maternal - 22890305 Yatsenko SA , et al. (2012)
- - copy_number_gain Familial Paternal - 22890305 Yatsenko SA , et al. (2012)
c.1901+27A>G - intron_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.3376C>T p.Pro1126Ser missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.915G>A p.Leu305%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.265A>G p.Lys89Glu missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1147C>T p.Arg383Ter stop_gained Unknown - Simplex 30982612 Gorman KM , et al. (2019)
C>A p.Leu1575Met missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.3043A>G p.Lys1015Glu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
G>A p.Arg2227Gln missense_variant Familial Paternal - 35350424 Viggiano M et al. (2022)
c.1799T>G p.Val600Gly missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.2908G>A p.Glu970Lys missense_variant Unknown - Simplex 38256266 Omri Bar et al. (2024)
c.3685G>A p.Gly1229Ser missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.5363C>G p.Thr1788Ser missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.6083G>A p.Arg2028Gln missense_variant Unknown - Simplex 38256266 Omri Bar et al. (2024)
c.390+1ins48 - splice_site_variant Unknown - Multiplex 35773312 Trifiletti R et al. (2022)
c.1721T>G p.Ile574Ser missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.6305G>T p.Arg2102Leu missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.6452C>T p.Ser2151Leu missense_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.4071G>A p.Thr1357= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.6192G>A p.Gln2064= synonymous_variant Unknown - Unknown 21703448 Klassen T , et al. (2011)
c.2899C>T p.Arg967Trp missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.6709G>A p.Ala2237Thr missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.6830C>T p.Thr2277Ile missense_variant Familial Paternal - 35350424 Viggiano M et al. (2022)
c.6928G>A p.Val2310Met missense_variant Familial Paternal - 35350424 Viggiano M et al. (2022)
c.4336G>A p.Ala1446Thr missense_variant Unknown - Simplex 31038196 Callaghan DB , et al. (2019)
c.394G>T p.Asp132Tyr missense_variant Familial Paternal Simplex 28867142 Krupp DR , et al. (2017)
c.3370A>G p.Ile1124Val missense_variant Familial Maternal Simplex 35668055 Teles E Silva AL et al. (2022)
c.3665del p.Leu1222ArgfsTer29 frameshift_variant Familial Both parents Multiplex 30982612 Gorman KM , et al. (2019)
c.4857+1G>C - splice_site_variant Familial and unknown Maternal and unknown Multiplex 30982612 Gorman KM , et al. (2019)
c.3573_3574del p.Gly1192CysfsTer5 frameshift_variant Familial and unknown Maternal and unknown Multiplex 30982612 Gorman KM , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

In a study of 20 unrelated children with variable phenotypes found to have gains in DNA copy number in the subtelomeric 9q34 region, seven were found to carry monogenic duplications encompassing the CACNA1B gene. Four of these children with monogenic CACNA1B duplications were diagnosed with ASD (Yatensko et al., 2012). A de novo missense variant that was predicted to be probably damaging was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014); however, this variant was also reported in dbSNP and ESP.

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

In a study of 20 unrelated children with variable phenotypes found to have gains in DNA copy number in the subtelomeric 9q34 region, seven were found to carry monogenic duplications encompassing the CACNA1B gene. Four of these children with monogenic CACNA1B duplications were diagnosed with ASD (Yatensko et al., 2012). A de novo missense variant that was predicted to be probably damaging was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014); however, this variant was also reported in dbSNP and ESP.

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

In a study of 20 unrelated children with variable phenotypes found to have gains in DNA copy number in the subtelomeric 9q34 region, seven were found to carry monogenic duplications encompassing the CACNA1B gene. Four of these children with monogenic CACNA1B duplications were diagnosed with ASD (Yatensko et al., 2012). A de novo missense variant that was predicted to be probably damaging was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014); however, this variant was also reported in dbSNP and ESP.

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

Decreased from 4 to 4

Description

In a study of 20 unrelated children with variable phenotypes found to have gains in DNA copy number in the subtelomeric 9q34 region, seven were found to carry monogenic duplications encompassing the CACNA1B gene. Four of these children with monogenic CACNA1B duplications were diagnosed with ASD (Yatensko et al., 2012). A de novo missense variant that was predicted to be probably damaging was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014); however, this variant was also reported in dbSNP and ESP.

Reports Added
[Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.2019] [Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
7/1/2018
icon
4

Increased from to 4

Description

In a study of 20 unrelated children with variable phenotypes found to have gains in DNA copy number in the subtelomeric 9q34 region, seven were found to carry monogenic duplications encompassing the CACNA1B gene. Four of these children with monogenic CACNA1B duplications were diagnosed with ASD (Yatensko et al., 2012). A de novo missense variant that was predicted to be probably damaging was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014); however, this variant was also reported in dbSNP and ESP.

Krishnan Probability Score

Score 0.606254301376

Ranking 319/25841 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 0.98260344313807

Ranking 2058/18225 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
Sanders TADA Score

Score 0.40778270450037

Ranking 289/18665 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
Zhang D Score

Score 0.4317891656242

Ranking 1099/20870 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.
Original Source
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