Human Gene Module / Chromosome 16 / SRRM2

SRRM2serine/arginine repetitive matrix 2

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
13 / 14
Rare Variants / Common Variants
41 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
16p13.3
Associated Disorders
-
Relevance to Autism

Numerous de novo variants in the SRRM2 gene have been identified in ASD probands, including two de novo loss-of-function (LoF) variants and a number of de novo missense variants (De Rubeis et al., 2014; Iossifov et al., 2014; Krumm et al., 2015; Sanders et al., 2015; Yuen et al., 2016; Yuen et al., 2017; Turner et al., 2017; Takata et al., 2018; Feliciano et al., 2019; Satterstrom et al., 2020). Cuinat et al., 2022 reported 22 individuals with loss-of-function variants in SRRM2 presenting with a neurodevelopmental syndrome characterized by developmental delay, intellectual disability, features of autism spectrum disorder or attention deficit hyperactivity disorder, overfriendliness, generalized hypotonia, overweight/obesity, and dysmorphic facial features.

Molecular Function

Enables C2H2 zinc finger domain binding activity and protein N-terminus binding activity. Involved in mRNA splicing, via spliceosome. Located in Cajal body and nuclear speck. Part of U2-type catalytic step 2 spliceosome and U2-type precatalytic spliceosome. Biomarker of Parkinson's disease.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
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SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SRRM2 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
4 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
5 Support Genome-wide characteristics of de novo mutations in autism Yuen RK et al. (2016) Yes -
6 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
7 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
8 Support Integrative Analyses of De Novo Mutations Provide Deeper Biological Insights into Autism Spectrum Disorder Takata A , et al. (2018) Yes -
9 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
10 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
11 Recent Recommendation - Cuinat S et al. (2022) No Autistic features, ADHD features
12 Support - Zhou X et al. (2022) Yes -
13 Support - Yuan B et al. (2023) Yes -
14 Support - Soo-Whee Kim et al. (2024) Yes -
Rare Variants   (41)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 35567594 Cuinat S et al. (2022)
c.187A>T p.Lys63Ter stop_gained De novo - - 36881370 Yuan B et al. (2023)
c.58C>T p.Gln20Ter stop_gained De novo - - 35567594 Cuinat S et al. (2022)
c.*14G>T - 3_prime_UTR_variant De novo - - 26402605 Sanders SJ , et al. (2015)
c.1882C>T p.Arg628Ter stop_gained De novo - - 35567594 Cuinat S et al. (2022)
c.3346C>T p.Gln1116Ter stop_gained De novo - - 35567594 Cuinat S et al. (2022)
c.4616C>A p.Ser1539Ter stop_gained De novo - - 35567594 Cuinat S et al. (2022)
c.4913C>G p.Ser1638Ter stop_gained De novo - - 35567594 Cuinat S et al. (2022)
c.5074C>T p.Arg1692Ter stop_gained De novo - - 35567594 Cuinat S et al. (2022)
c.6127C>T p.Arg2043Ter stop_gained De novo - - 35567594 Cuinat S et al. (2022)
c.6265C>T p.Arg2089Ter stop_gained De novo - - 35567594 Cuinat S et al. (2022)
c.-31-58C>T - intron_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.1033-388C>G - intron_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.85C>T p.Arg29Cys missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2203A>G p.Arg735Gly missense_variant De novo - - 39334436 Soo-Whee Kim et al. (2024)
c.2686C>T p.Pro896Ser missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.5147C>A p.Thr1716Asn missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.6509C>G p.Thr2170Arg missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.7875C>T p.Ser2625= synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2686C>T p.Pro896Ser missense_variant De novo - Simplex 27525107 Yuen RK et al. (2016)
c.6178C>T p.Arg2060Ter stop_gained De novo - Simplex 31452935 Feliciano P et al. (2019)
c.1467C>T p.Thr489= synonymous_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.4720C>T p.Arg1574Trp missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.4424G>A p.Arg1475Lys missense_variant De novo - Simplex 29346770 Takata A , et al. (2018)
c.6709dup p.Ala2237GlyfsTer22 frameshift_variant De novo - - 35567594 Cuinat S et al. (2022)
c.4736C>A p.Ser1579Tyr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.4533C>T p.Thr1511= synonymous_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.3551_3554del p.Lys1184ThrfsTer54 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.2214_2215del p.Arg739LysfsTer48 frameshift_variant De novo - - 35567594 Cuinat S et al. (2022)
c.2782_2785del p.Arg928AlafsTer13 frameshift_variant De novo - - 35567594 Cuinat S et al. (2022)
c.2970_2971del p.Gly991ValfsTer31 frameshift_variant De novo - - 35567594 Cuinat S et al. (2022)
c.4200_4203dup p.Ile1402GlufsTer8 frameshift_variant Unknown - - 35567594 Cuinat S et al. (2022)
c.6042_6043del p.Arg2015ProfsTer4 frameshift_variant De novo - - 35567594 Cuinat S et al. (2022)
c.7734-304_7734-303insAGGAGA - intron_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.3426_3427del p.Ser1143PhefsTer15 frameshift_variant De novo - - 35567594 Cuinat S et al. (2022)
c.4512_4578del p.Asn1506TrpfsTer20 frameshift_variant De novo - - 35567594 Cuinat S et al. (2022)
c.4528_4529del p.Leu1510TyrfsTer14 frameshift_variant De novo - - 35567594 Cuinat S et al. (2022)
c.5410_5411dup p.Ser1804ArgfsTer80 frameshift_variant Unknown - - 35567594 Cuinat S et al. (2022)
c.7254_7257del p.Met2419ProfsTer43 frameshift_variant De novo - - 35567594 Cuinat S et al. (2022)
c.2782_2785del p.Arg928AlafsTer13 frameshift_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.2782_2785del p.Arg928AlafsTer13 frameshift_variant Familial Paternal - 35567594 Cuinat S et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Score Delta: Score remained at 2S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
icon
2S

Increased from to 2S

Krishnan Probability Score

Score 0.4879846156043

Ranking 6851/25841 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
Iossifov Probability Score

Score 0.976

Ranking 48/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Zhang D Score

Score 0.59075895498383

Ranking 112/20870 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 SRRM2(1 CNVs)
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16p13.3 73 Deletion-Duplication 103  /  544
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