Human Gene Module / Chromosome 14 / SOS2

SOS2SOS Ras/Rho guanine nucleotide exchange factor 2

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
5 / 7
Rare Variants / Common Variants
5 / 0
Aliases
-
Associated Syndromes
Noonan syndrome-9
Chromosome Band
14q21.3
Associated Disorders
-
Relevance to Autism

SOS2 was identified as an ASD candidate gene in Wilfert et al., 2021 based on the discovery of private likely gene-disruptive (LGD) variants in this highly constrained (pLI 0.99) gene that were exclusively transmitted to three ASD probands in two independent families and its interconnectedness with other ASD candidate genes in protein-protein interaction (PPI) networks in this report. A de novo missense variant in this gene had previously been identified in an ASD proband from the Autism Sequencing Consortium (Satterstrom et al., 2020).

Molecular Function

This gene encodes a regulatory protein that is involved in the positive regulation of ras proteins. Heterozygous mutations in the SOS2 gene are associated with Noonan syndrome-9 (NS9; OMIM 616559), an autosomal dominant disorder characterized by short stature, craniofacial dysmorphism, short and/or webbed neck, cardiac abnormalities, cryptorchidism, and coagulation defects.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SOS2 (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Rare variants in SOS2 and LZTR1 are associated with Noonan syndrome Yamamoto GL , et al. (2015) No -
2 Support - Cordeddu V et al. (2015) No -
3 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Primary - Wilfert AB et al. (2021) Yes -
5 Support - Krgovic D et al. (2022) Yes -
6 Support - Zhou X et al. (2022) Yes -
7 Positive Association - Yi Yang et al. () Yes -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.702G>A p.Leu234= synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.673C>T p.Arg225Ter stop_gained Familial - - 34312540 Wilfert AB et al. (2021)
c.791C>A p.Thr264Lys missense_variant De novo - - 35813072 Krgovic D et al. (2022)
c.3860C>G p.Pro1287Arg missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.133_136del p.Leu45IlefsTer6 frameshift_variant Familial - - 34312540 Wilfert AB et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

10/1/2022
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1

Increased from to 1

Krishnan Probability Score

Score 0.49655581506671

Ranking 2569/25841 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 0.99942784097124

Ranking 961/18225 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 0.94335118376999

Ranking 15654/18665 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 0.16532960036093

Ranking 4883/20870 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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