Human Gene Module / Chromosome 12 / ATP6V0A2

ATP6V0A2ATPase H+ transporting V0 subunit a2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
4 / 5
Rare Variants / Common Variants
21 / 0
Aliases
ATP6V0A2, A2,  ARCL,  ARCL2A,  ATP6A2,  ATP6N1D,  J6B7,  RTF,  STV1,  TJ6,  TJ6M,  TJ6S,  VPH1,  WSS
Associated Syndromes
-
Chromosome Band
12q24.31
Associated Disorders
-
Relevance to Autism

Rare inherited loss-of-function and damaging missense variants in the ATP6V0A2 gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015; targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified additional rare inherited variants in this gene in ASD probands. Subsequent Transmission and De Novo Association (TADA) analysis In Guo et al., 2017 identified ATP6V0A2 as an ASD candidate gene with a PTADA of 0.007146 in the Chinese ASD case-control cohort and a PTADA of 0.007251 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium.

Molecular Function

The protein encoded by this gene is a subunit of the vacuolar ATPase (v-ATPase), an heteromultimeric enzyme that is present in intracellular vesicles and in the plasma membrane of specialized cells, and which is essential for the acidification of diverse cellular components. V-ATPase is comprised of a membrane peripheral V(1) domain for ATP hydrolysis, and an integral membrane V(0) domain for proton translocation. The subunit encoded by this gene is a component of the V(0) domain. Biallelic mutations in the ATP6V0A2 gene are associated with autosomal recessive cutis laxa type IIA (ARCL2A; OMIM 219200) and wrinkly skin syndrome (OMIM 278250).

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ATP6V0A2 (5 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
2 Recent Recommendation Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
3 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
4 Support - Woodbury-Smith M et al. (2022) Yes -
5 Support - Balasar et al. (2023) No -
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.482T>G p.Leu161Trp missense_variant Familial - - 28831199 Li J , et al. (2017)
c.2384C>T p.Ala795Val missense_variant Familial - - 28831199 Li J , et al. (2017)
c.2477A>C p.Gln826Pro missense_variant Familial - - 28831199 Li J , et al. (2017)
c.1563del p.Pro522LeufsTer26 frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.2557G>A p.Asp853Asn missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.353_354del p.Leu118GlnfsTer26 frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.1039-1G>A - splice_site_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2466-2A>G - splice_site_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.2466-2A>G - splice_site_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.65C>G p.Ala22Gly missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.422G>A p.Arg141His missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.422G>T p.Arg141Leu missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.503G>C p.Arg168Thr missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.776G>A p.Arg259Gln missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1112G>A p.Arg371His missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.1609T>G p.Trp537Gly missense_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.1975T>C p.Ser659Pro missense_variant Familial Paternal Simplex 25961944 Krumm N , et al. (2015)
c.2055+4A>G - splice_region_variant Familial Both parents Simplex 37524782 Balasar et al. (2023)
c.1560_1561insTGCAAAGG p.Ile521CysfsTer30 frameshift_variant Familial - - 28831199 Li J , et al. (2017)
c.78dup p.Ser27GlnfsTer28 frameshift_variant Familial Maternal Simplex 25961944 Krumm N , et al. (2015)
c.390_397dup p.Arg133ThrfsTer3 frameshift_variant Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Rare inherited loss-of-function and damaging missense variants in the ATP6V0A2 gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015; targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified additional rare inherited variants in this gene in ASD probands. Subsequent Transmission and De Novo Association (TADA) analysis In Guo et al., 2017 identified ATP6V0A2 as an ASD candidate gene with a PTADA of 0.007146 in the Chinese ASD case-control cohort and a PTADA of 0.007251 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ATP6V0A2 gene are associated with autosomal recessive cutis laxa type IIA (ARCL2A; OMIM 219200) and wrinkly skin syndrome (OMIM 278250).

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

Rare inherited loss-of-function and damaging missense variants in the ATP6V0A2 gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015; targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified additional rare inherited variants in this gene in ASD probands. Subsequent Transmission and De Novo Association (TADA) analysis In Guo et al., 2017 identified ATP6V0A2 as an ASD candidate gene with a PTADA of 0.007146 in the Chinese ASD case-control cohort and a PTADA of 0.007251 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ATP6V0A2 gene are associated with autosomal recessive cutis laxa type IIA (ARCL2A; OMIM 219200) and wrinkly skin syndrome (OMIM 278250).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Rare inherited loss-of-function and damaging missense variants in the ATP6V0A2 gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015; targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified additional rare inherited variants in this gene in ASD probands. Subsequent Transmission and De Novo Association (TADA) analysis In Guo et al., 2017 identified ATP6V0A2 as an ASD candidate gene with a PTADA of 0.007146 in the Chinese ASD case-control cohort and a PTADA of 0.007251 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ATP6V0A2 gene are associated with autosomal recessive cutis laxa type IIA (ARCL2A; OMIM 219200) and wrinkly skin syndrome (OMIM 278250).

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Rare inherited loss-of-function and damaging missense variants in the ATP6V0A2 gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015; targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified additional rare inherited variants in this gene in ASD probands. Subsequent Transmission and De Novo Association (TADA) analysis In Guo et al., 2017 identified ATP6V0A2 as an ASD candidate gene with a PTADA of 0.007146 in the Chinese ASD case-control cohort and a PTADA of 0.007251 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ATP6V0A2 gene are associated with autosomal recessive cutis laxa type IIA (ARCL2A; OMIM 219200) and wrinkly skin syndrome (OMIM 278250).

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
7/1/2017
icon
4

Increased from to 4

Description

Rare inherited loss-of-function and damaging missense variants in the ATP6V0A2 gene were identified in ASD probands from the Simons Simplex Collection in Krumm et al., 2015; targeted sequencing of 536 Chinese ASD probands and 1457 Chinese controls in Guo et al., 2017 identified additional rare inherited variants in this gene in ASD probands. Subsequent Transmission and De Novo Association (TADA) analysis In Guo et al., 2017 identified ATP6V0A2 as an ASD candidate gene with a PTADA of 0.007146 in the Chinese ASD case-control cohort and a PTADA of 0.007251 in a combined cohort of Chinese ASD probands and controls, as well as ASD probands and controls from the Simons Simplex Collection and the Autism Sequencing Consortium. Biallelic mutations in the ATP6V0A2 gene are associated with autosomal recessive cutis laxa type IIA (ARCL2A; OMIM 219200) and wrinkly skin syndrome (OMIM 278250).

Krishnan Probability Score

Score 0.4469860590425

Ranking 14249/25841 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 4.7381062923334E-6

Ranking 14506/18225 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 0.87033495876547

Ranking 4319/18665 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 -0.074230708972227

Ranking 11342/20870 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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