Human Gene Module / Chromosome 12 / AGAP2

AGAP2ArfGAP with GTPase domain, ankyrin repeat and PH domain 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 6
Rare Variants / Common Variants
15 / 0
EAGLE Score
3.25
Limited Learn More
Aliases
AGAP2, CENTG1,  GGAP2,  PIKE
Associated Syndromes
-
Chromosome Band
12q14.1
Associated Disorders
-
Genetic Category
Rare Single Gene Mutation
Relevance to Autism

De novo missense variants in the AGAP2 gene have previously been identified in ASD cases (De Rubeis et al., 2014; Iossifov et al., 2014). An additional de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband from a multiplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of multiple de novo missense variants in ASD cases, a z-score >2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), AGAP2 was determined to be an ASD candidate gene in Yuen et al., 2017.

Molecular Function

The protein encoded by this gene belongs to the centaurin gamma-like family. It mediates anti-apoptotic effects of nerve growth factor by activating nuclear phosphoinositide 3-kinase.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to AGAP2 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Recent Recommendation Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
4 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
5 Support - Rodin RE et al. (2021) Yes -
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (15)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.450G>A p.Trp150Ter stop_gained De novo - - 33432195 Rodin RE et al. (2021)
c.1401+1G>T - splice_site_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.1432G>A p.Val478Ile missense_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.1483G>T p.Gly495Trp missense_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.1876G>A p.Glu626Lys missense_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.2057G>A p.Arg686Gln missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2506A>G p.Lys836Glu missense_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.2521C>G p.Pro841Ala missense_variant Unknown - - 25363760 De Rubeis S , et al. (2014)
c.2427G>A p.Thr809%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.901C>G p.Pro301Ala missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1214C>T p.Pro405Leu missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2755A>G p.Ser919Gly missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1819G>A p.Asp607Asn missense_variant Familial Paternal - 25363760 De Rubeis S , et al. (2014)
c.1414G>A p.Ala472Thr missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1394G>A;c.2402G>A p.Arg465Gln;p.Arg801Gln missense_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo missense variants in the AGAP2 gene have previously been identified in ASD cases (De Rubeis et al., 2014; Iossifov et al., 2014). An additional de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband from a multiplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of multiple de novo missense variants in ASD cases, a z-score > 2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), AGAP2 was determined to be an ASD candidate gene in Yuen et al., 2017.

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.

1/1/2021
2
icon
2

Score remained at 2

Description

De novo missense variants in the AGAP2 gene have previously been identified in ASD cases (De Rubeis et al., 2014; Iossifov et al., 2014). An additional de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband from a multiplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of multiple de novo missense variants in ASD cases, a z-score > 2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), AGAP2 was determined to be an ASD candidate gene in Yuen et al., 2017.

Reports Added
[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

De novo missense variants in the AGAP2 gene have previously been identified in ASD cases (De Rubeis et al., 2014; Iossifov et al., 2014). An additional de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband from a multiplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of multiple de novo missense variants in ASD cases, a z-score > 2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), AGAP2 was determined to be an ASD candidate gene in Yuen et al., 2017.

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

Decreased from 3 to 3

Description

De novo missense variants in the AGAP2 gene have previously been identified in ASD cases (De Rubeis et al., 2014; Iossifov et al., 2014). An additional de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband from a multiplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of multiple de novo missense variants in ASD cases, a z-score > 2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), AGAP2 was determined to be an ASD candidate gene in Yuen et al., 2017.

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
4/1/2017
icon
3

Increased from to 3

Description

De novo missense variants in the AGAP2 gene have previously been identified in ASD cases (De Rubeis et al., 2014; Iossifov et al., 2014). An additional de novo missense variant in this gene was identified by whole genome sequencing in an ASD proband from a multiplex family as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of multiple de novo missense variants in ASD cases, a z-score >2.0 for missense mutations, and a higher-than expected mutation rate (a false discovery rate < 15%), AGAP2 was determined to be an ASD candidate gene in Yuen et al., 2017.

Krishnan Probability Score

Score 0.50653305387088

Ranking 1884/25841 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 0.99921890206789

Ranking 1019/18225 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 0.32741055718145

Ranking 202/18665 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 -0.20679804880334

Ranking 15572/20870 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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