Human Gene Module / Chromosome 22 / CACNG2

CACNG2calcium voltage-gated channel auxiliary subunit gamma 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 6
Rare Variants / Common Variants
4 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
22q12.3
Associated Disorders
-
Relevance to Autism

Analysis of whole-exome sequencing data from 13,091 individuals diagnosed with autism recruited from the SSC, SPARK, and iPSYCH cohorts, 19,488 first-degree relatives of individuals with autism from the SSC and SPARK cohorts, and 194,070 individuals identified from unselected population samples from the iPSYCH and UK Biobank cohorts in Rolland et al., 2023 identified CACNG2 as a novel ASD candidate gene intolerant to loss-of-function variants with an odds ratio greater than 10. Several de novo variants in the CACNG2 gene, including two de novo missense variants and a de novo intragenic deletion that was predicted to result in an in-frame deletion of 30 amino acids from the extracellular AMPA receptor-binding domain, have been identified in ASD probands (Brandler et al., 2016; Lim et al., 2017; Yuan et al., 2023). A de novo missense variant in the CACNG2 gene (p.Val143Leu) was identified in a patient presenting with sporadic non-syndromic intellectual disability in Hamdan et al., 2011; this variant was experimentally demonstrated to result in reduced binding to GluR1 or GluR2 AMPAR subunits, reduced GluR1 cell surface expression, and reduced miniEPSC amplitude and frequency in transfected hippocampal neurons. Subsequent characterization of a knock-in mouse with the p.Val143Leu variant in Caldeira et al., 2022 demonstrated that these mice displayed cognitive and social deficits, as well as hippocampal synaptic transmission defects.

Molecular Function

The protein encoded by this gene is a type I transmembrane AMPA receptor regulatory protein (TARP). TARPs regulate both trafficking and channel gating of the AMPA receptors. The AMPA subtype of ionotropic glutamate receptors are ligand gated ion channels that are typically activated by glutamate released from presynaptic neuron terminals and mediate fast neurotransmission in excitatory synapses. TARPs thus play an important role in synaptic plasticity, learning and memory.

External Links
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Reports related to CACNG2 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability Hamdan FF , et al. (2011) No -
2 Support Frequency and Complexity of De Novo Structural Mutation in Autism Brandler WM , et al. (2016) Yes -
3 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
4 Support - Caldeira GL et al. (2022) No -
5 Support - Yuan B et al. (2023) Yes -
6 Primary - Rolland T et al. (2023) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 27018473 Brandler WM , et al. (2016)
c.710G>C p.Ser237Thr missense_variant De novo - - 36881370 Yuan B et al. (2023)
c.707G>C p.Arg236Pro missense_variant De novo - - 28714951 Lim ET , et al. (2017)
c.427G>C p.Val143Leu missense_variant De novo - Simplex 21376300 Hamdan FF , et al. (2011)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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.

7/1/2023
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.56874958356678

Ranking 1099/25841 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 0.95805600333691

Ranking 2565/18225 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 0.92960722726576

Ranking 11211/18665 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 -0.21833952019596

Ranking 15803/20870 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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