Human Gene Module / Chromosome 8 / RAB2A

RAB2ARAB2A, member RAS oncogene family

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
5 / 0
Aliases
RAB2A, LHX,  RAB2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
8q12.1-q12.2
Associated Disorders
-
Relevance to Autism

Two de novo variants (a nonsense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the RAB2A gene in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012). 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 4.48E-06 (Takata et al., 2016).

Molecular Function

The protein encoded by this gene belongs to the Rab family, members of which are small molecular weight guanosine triphosphatases (GTPases) that contain highly conserved domains involved in GTP binding and hydrolysis. The Rabs are membrane-bound proteins, involved in vesicular fusion and trafficking. This protein is a resident of pre-Golgi intermediates, and is required for protein transport from the endoplasmic reticulum (ER) to the Golgi complex.

Reports related to RAB2A (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Integrative genome-wide association analysis of cytoarchitectural abnormalities in the prefrontal cortex of psychiatric disorders. Kim S and Webster MJ (2010) No -
2 Primary De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Sanders SJ , et al. (2012) Yes -
3 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
4 Support Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
5 Support RAB2A Polymorphism impacts prefrontal morphology, functional connectivity, and working memory. Li J , et al. (2015) No -
6 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Takata A , et al. (2016) No -
7 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
8 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder. Lim ET , et al. (2017) Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.136C>T p.Arg46Ter stop_gained De novo NA Simplex 22495306 Sanders SJ , et al. (2012)
c.290+1G>A - splice_site_variant Familial Maternal - 25363760 De Rubeis S , et al. (2014)
c.549T>G p.Ala183= missense_variant De novo NA Multiplex 28714951 Lim ET , et al. (2017)
c.341C>T p.Ala114Val missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.129C>T p.Phe43= synonymous_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Two de novo variants (a nonsense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the RAB2A gene in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012). 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 4.48E-06 (Takata et al., 2016). Expression SNP (eSNP) analysis in the prefrontal cortex (PFC) of subjects with psychiatric disorders indicated that RAB2A was associated with the density of calbindin-positive neurons (Kim and Webster, 2011). A RAB2A haplotype associated with improved white matter accuracy, increased cortical thickness in the left inferior frontal gyrus, and decreased functional connectivity between the left inferior frontal gyrus and the left dorsolateral PFC in a large sample of healthy Han Chinese subjects (Li et al., 2015).

Score Delta: Score remained at 3

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Two de novo variants (a nonsense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the RAB2A gene in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012). 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 4.48E-06 (Takata et al., 2016). Expression SNP (eSNP) analysis in the prefrontal cortex (PFC) of subjects with psychiatric disorders indicated that RAB2A was associated with the density of calbindin-positive neurons (Kim and Webster, 2011). A RAB2A haplotype associated with improved white matter accuracy, increased cortical thickness in the left inferior frontal gyrus, and decreased functional connectivity between the left inferior frontal gyrus and the left dorsolateral PFC in a large sample of healthy Han Chinese subjects (Li et al., 2015).

Reports Added
[New Scoring Scheme]
7/1/2018
4.5 + acc
icon
3

Decreased from 4.5 + acc to 3

Description

Two de novo variants (a nonsense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the RAB2A gene in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012). 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 4.48E-06 (Takata et al., 2016). Expression SNP (eSNP) analysis in the prefrontal cortex (PFC) of subjects with psychiatric disorders indicated that RAB2A was associated with the density of calbindin-positive neurons (Kim and Webster, 2011). A RAB2A haplotype associated with improved white matter accuracy, increased cortical thickness in the left inferior frontal gyrus, and decreased functional connectivity between the left inferior frontal gyrus and the left dorsolateral PFC in a large sample of healthy Han Chinese subjects (Li et al., 2015).

4/1/2018
3
icon
4.5 + acc

Increased from 3 to 4.5 + acc

Description

3

7/1/2017
3
icon
3

Increased from 3 to 3

Description

Two de novo variants (a nonsense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the RAB2A gene in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012). 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 4.48E-06 (Takata et al., 2016). Expression SNP (eSNP) analysis in the prefrontal cortex (PFC) of subjects with psychiatric disorders indicated that RAB2A was associated with the density of calbindin-positive neurons (Kim and Webster, 2011). A RAB2A haplotype associated with improved white matter accuracy, increased cortical thickness in the left inferior frontal gyrus, and decreased functional connectivity between the left inferior frontal gyrus and the left dorsolateral PFC in a large sample of healthy Han Chinese subjects (Li et al., 2015).

10/1/2016
3
icon
3

Increased from 3 to 3

Description

Two de novo variants (a nonsense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the RAB2A gene in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012). 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 4.48E-06 (Takata et al., 2016). Expression SNP (eSNP) analysis in the prefrontal cortex (PFC) of subjects with psychiatric disorders indicated that RAB2A was associated with the density of calbindin-positive neurons (Kim and Webster, 2011). A RAB2A haplotype associated with improved white matter accuracy, increased cortical thickness in the left inferior frontal gyrus, and decreased functional connectivity between the left inferior frontal gyrus and the left dorsolateral PFC in a large sample of healthy Han Chinese subjects (Li et al., 2015).

7/1/2016
3
icon
3

Increased from 3 to 3

Description

Two de novo variants (a nonsense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the RAB2A gene in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012). 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 4.48E-06 (Takata et al., 2016). Expression SNP (eSNP) analysis in the prefrontal cortex (PFC) of subjects with psychiatric disorders indicated that RAB2A was associated with the density of calbindin-positive neurons (Kim and Webster, 2011). A RAB2A haplotype associated with improved white matter accuracy, increased cortical thickness in the left inferior frontal gyrus, and decreased functional connectivity between the left inferior frontal gyrus and the left dorsolateral PFC in a large sample of healthy Han Chinese subjects (Li et al., 2015).

4/1/2016
icon
3

Increased from to 3

Description

Two de novo variants (a nonsense variant and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator) were observed in the RAB2A gene in ASD probands from the Simons Simplex Collection (Sanders et al., 2012; Iossifov et al., 2012). 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 4.48E-06 (Takata et al., 2016). Expression SNP (eSNP) analysis in the prefrontal cortex (PFC) of subjects with psychiatric disorders indicated that RAB2A was associated with the density of calbindin-positive neurons (Kim and Webster, 2011). A RAB2A haplotype associated with improved white matter accuracy, increased cortical thickness in the left inferior frontal gyrus, and decreased functional connectivity between the left inferior frontal gyrus and the left dorsolateral PFC in a large sample of healthy Han Chinese subjects (Li et al., 2015).

Krishnan Probability Score

Score 0.49238678733897

Ranking 4564/25841 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.
ExAC Score

Score 0.97073551268808

Ranking 2343/18225 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
Sanders TADA Score

Score 0.20494646251838

Ranking 114/18665 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).
Zhang D Score

Score -0.45085343755858

Ranking 18837/20870 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.
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