Human Gene Module / Chromosome 3 / ACAP2

ACAP2ArfGAP with coiled-coil, ankyrin repeat and PH domains 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 5
Rare Variants / Common Variants
7 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
3q29
Associated Disorders
-
Relevance to Autism

Meta-analysis of CNV data from 11,614 affected individuals with NDDs and 4,031 controls individuals from the SFARI database, followed by the identification of driver risk genes within identified NDD-risk CNV loci, in Azidane et al., 2024 found that ACAP2 was a high confidence NDD-risk gene located in the 3q29 locus; furthermore, deletions of this gene were found to be transmitted to all children with ASD in four families from the iHart cohort in the same report. De novo missense variants in ACAP2 have also been identified in ASD probands (Satterstrom et al., 2020; Zhou et al., 2022).

Molecular Function

The protein encoded by this gene is a GTPase-activating protein (GAP) for ADP ribosylation factor 6 (ARF6) that acts upstream of or within the actin filament-based process and is located in membrane ruffles. Bhat et al., 2020 reported that ACAP2 was required to promote tunneling nanotubes and vesicle trafficking in neuronal cell lines.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ACAP2 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
2 Support - Shaarvari Bhat et al. (2020) No -
3 Support - Zhou X et al. (2022) Yes -
4 Primary - Sara Azidane et al. (2024) No ASD
5 Support - Ashlesha Gogate et al. (2024) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.467C>T p.Thr156Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2185G>A p.Ala729Thr missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Maternal Simplex 38850022 Sara Azidane et al. (2024)
- - copy_number_loss Familial Maternal Multiplex 38850022 Sara Azidane et al. (2024)
- - copy_number_loss Familial Paternal Multiplex 38850022 Sara Azidane et al. (2024)
c.523C>T p.Leu175Phe missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.208T>G p.Ser70Ala missense_variant Unknown Not maternal Simplex 39632905 Ashlesha Gogate et al. (2024)
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.

10/1/2024
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.41142967328497

Ranking 22442/25841 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 0.99991818497578

Ranking 653/18225 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 0.9376386737787

Ranking 13592/18665 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 0.31085147373317

Ranking 2577/20870 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
CNVs associated with ACAP2(1 CNVs)
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3q29 72 Deletion-Duplication 107  /  499
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