Human Gene Module / Chromosome 10 / CACNB2

CACNB2Calcium channel, voltage-dependent, beta 2 subunit

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
11 / 12
Rare Variants / Common Variants
14 / 2
Aliases
CACNB2, RP11-383B4.2,  CACNLB2,  CAVB2,  MYSB, CACNB2
Associated Syndromes
-
Chromosome Band
10p12.33-p12.31
Associated Disorders
EPS
Relevance to Autism

Three rare missense variants in the CACNB2 gene were identified in ASD probands from the Autism Genetic Resource Exchange (AGRE); while these variants showed incomplete segregation with ASD in the probands' respective families, all three variants altered time-dependent inactivation of Ca2+ channels in whole-cell patch-clamp recordings of HEK293 cells expressing mutant CACNB2 (Breitenkamp et al., 2014).

Molecular Function

This gene encodes a subunit of a voltage-dependent calcium channel protein that is a member of the voltage-gated calcium channel superfamily. The beta subunit of voltage-dependent calcium channels contributes to the function of the calcium channel by increasing peak calcium current, shifting the voltage dependencies of activation and inactivation, modulating G protein inhibition and controlling the alpha-1 subunit membrane targeting. Mutations in this gene are associated with Brugada syndrome 4 (BRGDA4) [MIM:611876], a heart disease characterized by the association of Brugada syndrome with shortened QT intervals.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CACNB2 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis Cross-Disorder Group of the Psychiatric Genomics Consortium (2013) Yes -
2 Primary Rare mutations of CACNB2 found in autism spectrum disease-affected families alter calcium channel function Breitenkamp AF , et al. (2014) Yes Epilepsy
3 Support Whole-genome sequencing of quartet families with autism spectrum disorder Yuen RK , et al. (2015) Yes -
4 Positive Association Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection Pardias AF , et al. (2018) No -
5 Support Autism-associated mutations in the Ca V ? 2 calcium-channel subunit increase Ba 2+-currents and lead to differential modulation by the RGK-protein Gem Despang P , et al. (2019) Yes -
6 Support A New Homozygous CACNB2 Mutation has Functional Relevance and Supports a Role for Calcium Channels in Autism Spectrum Disorder Graziano C et al. (2020) Yes -
7 Support - Woodbury-Smith M et al. (2022) Yes -
8 Support - Viggiano M et al. (2022) Yes -
9 Support - Teles E Silva AL et al. (2022) Yes -
10 Support - Zhou X et al. (2022) Yes -
11 Support - Trus M et al. (2022) Yes -
12 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (14)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1246C>T p.Leu416Phe missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.123A>G p.Ser41%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.5T>A p.Val2Asp missense_variant De novo - Multiplex 25621899 Yuen RK , et al. (2015)
G>C p.Asp183His missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.1495C>G p.Gln499Glu missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.675G>T p.Lys225Asn missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.1192C>T p.Leu398Phe missense_variant Familial Maternal - 35350424 Viggiano M et al. (2022)
c.1652G>C p.Arg551Thr missense_variant Familial Paternal - 35350424 Viggiano M et al. (2022)
c.169-1G>A - splice_site_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.208C>T p.Arg70Cys missense_variant Familial Both parents Simplex 32506348 Graziano C et al. (2020)
c.334G>A p.Gly167Ser missense_variant Familial Maternal Multiplex 24752249 Breitenkamp AF , et al. (2014)
c.425C>T p.Ser142Phe missense_variant Familial Paternal Multiplex 24752249 Breitenkamp AF , et al. (2014)
c.553T>C p.Phe240Leu missense_variant Familial Paternal Multiplex 24752249 Breitenkamp AF , et al. (2014)
c.1975C>T p.Arg659Cys missense_variant Familial Paternal Simplex 35668055 Teles E Silva AL et al. (2022)
Common Variants   (2)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.169-42179T>G;c.250-42179T>G;c.190-42179T>G;c.172-42179T>G;c.334-42179T>G - intron_variant - - - 29483656 Pardias AF , et al. (2018)
c.48+51682T>C;c.130-88925T>C;c.214-88925T>C T/C intron_variant - - - 23453885 Cross-Disorder Group of the Psychiatric Genomics Consortium (2013)
SFARI Gene score
2

Strong Candidate

Three rare missense variants in the CACNB2 gene were identified in ASD probands from the Autism Genetic Resource Exchange (AGRE). These variants showed incomplete segregation with ASD in the probands' respective families but were shown to be functional (altered time-dependent inactivation of Ca2+ channels in whole-cell patch-clamp recordings of HEK293 cells expressing mutant CACNB2). While these variants were absent in 259 ethnically matched controls, a rigorous statistical comparison with the mutation frequency in controls was not performed to demonstrate statistical significance (PMID 24752249).

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.

7/1/2020
2
icon
2

Score remained at 2

Description

Three rare missense variants in the CACNB2 gene were identified in ASD probands from the Autism Genetic Resource Exchange (AGRE). These variants showed incomplete segregation with ASD in the probands' respective families but were shown to be functional (altered time-dependent inactivation of Ca2+ channels in whole-cell patch-clamp recordings of HEK293 cells expressing mutant CACNB2). While these variants were absent in 259 ethnically matched controls, a rigorous statistical comparison with the mutation frequency in controls was not performed to demonstrate statistical significance (PMID 24752249).

Reports Added
[A New Homozygous CACNB2 Mutation has Functional Relevance and Supports a Role for Calcium Channels in Autism Spectrum Disorder2020]
1/1/2020
2
icon
2

Score remained at 2

Description

Three rare missense variants in the CACNB2 gene were identified in ASD probands from the Autism Genetic Resource Exchange (AGRE). These variants showed incomplete segregation with ASD in the probands' respective families but were shown to be functional (altered time-dependent inactivation of Ca2+ channels in whole-cell patch-clamp recordings of HEK293 cells expressing mutant CACNB2). While these variants were absent in 259 ethnically matched controls, a rigorous statistical comparison with the mutation frequency in controls was not performed to demonstrate statistical significance (PMID 24752249).

Reports Added
[Autism-associated mutations in the CaV2 calcium-channel subunit increase Ba2+-currents and lead to differential modulation by the RGK-protein Gem.2019]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Three rare missense variants in the CACNB2 gene were identified in ASD probands from the Autism Genetic Resource Exchange (AGRE). These variants showed incomplete segregation with ASD in the probands' respective families but were shown to be functional (altered time-dependent inactivation of Ca2+ channels in whole-cell patch-clamp recordings of HEK293 cells expressing mutant CACNB2). While these variants were absent in 259 ethnically matched controls, a rigorous statistical comparison with the mutation frequency in controls was not performed to demonstrate statistical significance (PMID 24752249).

Reports Added
[New Scoring Scheme]
1/1/2015
3
icon
3

Decreased from 3 to 3

Description

Three rare missense variants in the CACNB2 gene were identified in ASD probands from the Autism Genetic Resource Exchange (AGRE). These variants showed incomplete segregation with ASD in the probands' respective families but were shown to be functional (altered time-dependent inactivation of Ca2+ channels in whole-cell patch-clamp recordings of HEK293 cells expressing mutant CACNB2). While these variants were absent in 259 ethnically matched controls, a rigorous statistical comparison with the mutation frequency in controls was not performed to demonstrate statistical significance (PMID 24752249).

Reports Added
[Whole-genome sequencing of quartet families with autism spectrum disorder.2015]
7/1/2014
No data
icon
3

Increased from No data to 3

Description

Three rare missense variants in the CACNB2 gene were identified in ASD probands from the Autism Genetic Resource Exchange (AGRE). These variants showed incomplete segregation with ASD in the probands' respective families but were shown to be functional (altered time-dependent inactivation of Ca2+ channels in whole-cell patch-clamp recordings of HEK293 cells expressing mutant CACNB2). While these variants were absent in 259 ethnically matched controls, a rigorous statistical comparison with the mutation frequency in controls was not performed to demonstrate statistical significance (PMID 24752249).

4/1/2014
No data
icon
3

Increased from No data to 3

Description

Three rare missense variants in the CACNB2 gene were identified in ASD probands from the Autism Genetic Resource Exchange (AGRE). These variants showed incomplete segregation with ASD in the probands' respective families but were shown to be functional (altered time-dependent inactivation of Ca2+ channels in whole-cell patch-clamp recordings of HEK293 cells expressing mutant CACNB2). While these variants were absent in 259 ethnically matched controls, a rigorous statistical comparison with the mutation frequency in controls was not performed to demonstrate statistical significance (PMID 24752249).

Krishnan Probability Score

Score 0.75194393939664

Ranking 34/25841 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 0.0018203378419392

Ranking 11339/18225 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 0.90780440406327

Ranking 7246/18665 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 15

Ranking 128/461 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
Zhang D Score

Score 0.12636285048559

Ranking 5610/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
RAD1 RAD1 homolog (S. pombe) Human Protein Binding 5810 O60671
REM1 GTP-binding protein REM 1 Human Protein Binding 28954 O75628
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