Human Gene Module / Chromosome 11 / PPP2R1B

PPP2R1Bprotein phosphatase 2 regulatory subunit A, beta

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 8
Rare Variants / Common Variants
8 / 0
Aliases
PPP2R1B, PP2A-Abeta,  PR65B
Associated Syndromes
Tourette syndrome
Chromosome Band
11q23.1
Associated Disorders
-
Relevance to Autism

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the PPP2R1B gene in ASD probands (Sanders et al., 2012; Fromer et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 9.60E-04 (Takata et al., 2016).

Molecular Function

This gene encodes for the PR65 subunit of protein phosphatase 2A, which serves as a scaffolding molecule to coordinate the assembly of the catalytic subunit and a variable regulatory B subunit.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PPP2R1B (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo mutations revealed by whole-exome sequencing are strongly associated with autism Sanders SJ , et al. (2012) Yes -
2 Support De novo mutations in schizophrenia implicate synaptic networks Fromer M , et al. (2014) Yes -
3 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia Takata A , et al. (2016) No -
4 Positive Association De Novo Coding Variants Are Strongly Associated with Tourette Disorder Willsey AJ , et al. (2017) No -
5 Support Both rare and common genetic variants contribute to autism in the Faroe Islands Leblond CS , et al. (2019) Yes -
6 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
7 Support Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort Wu H , et al. (2019) Yes Macrocephaly
8 Support - Cirnigliaro M et al. (2023) Yes -
Rare Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.333G>T p.Val111= synonymous_variant De novo - - 24463507 Fromer M , et al. (2014)
c.808C>T p.Arg270Cys missense_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.781C>T p.Arg261Ter stop_gained Familial Maternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.632_635del p.Asp211ValfsTer2 frameshift_variant Familial Maternal Simplex 31674007 Wu H , et al. (2019)
c.344_345del p.Val115GlyfsTer3 frameshift_variant Familial Paternal Simplex 30675382 Leblond CS , et al. (2019)
c.343_344del p.Val115CysfsTer3 frameshift_variant Unknown Not paternal Simplex 30675382 Leblond CS , et al. (2019)
c.343_344del p.Val115CysfsTer3 frameshift_variant Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1352A>C;c.1541A>C;c.1598A>C;c.A1733A>C p.Lys451Thr;p.Lys514Thr;p.Lys533Thr;p.Lys578Thr missense_variant De novo - Simplex 28472652 Willsey AJ , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the PPP2R1B gene in ASD probands (Sanders et al., 2012; Fromer et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 9.60E-04 (Takata et al., 2016).

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

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the PPP2R1B gene in ASD probands (Sanders et al., 2012; Fromer et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 9.60E-04 (Takata et al., 2016).

10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the PPP2R1B gene in ASD probands (Sanders et al., 2012; Fromer et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 9.60E-04 (Takata et al., 2016).

Reports Added
[Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.2019] [New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the PPP2R1B gene in ASD probands (Sanders et al., 2012; Fromer et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 9.60E-04 (Takata et al., 2016).

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

Decreased from 4 to 4

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the PPP2R1B gene in ASD probands (Sanders et al., 2012; Fromer et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 9.60E-04 (Takata et al., 2016).

Reports Added
[Both rare and common genetic variants contribute to autism in the Faroe Islands.2019]
4/1/2017
4
icon
4

Decreased from 4 to 4

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the PPP2R1B gene in ASD probands (Sanders et al., 2012; Fromer et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 9.60E-04 (Takata et al., 2016).

Reports Added
[De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [De novo mutations in schizophrenia implicate synaptic networks.2014] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016] [De Novo Coding Variants Are Strongly Associated with Tourette Disorder.2017]
4/1/2016
icon
4

Increased from to 4

Description

Two de novo variants (a missense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the PPP2R1B gene in ASD probands (Sanders et al., 2012; Fromer et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 9.60E-04 (Takata et al., 2016).

Krishnan Probability Score

Score 0.36622913591355

Ranking 23893/25841 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 2.1882863061729E-7

Ranking 15489/18225 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 0.65413072641042

Ranking 914/18665 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 -0.16540467190428

Ranking 14572/20870 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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