Human Gene Module / Chromosome 8 / RIMS2

RIMS2regulating synaptic membrane exocytosis 2

SFARI Gene Score
3S
Suggestive Evidence, Syndromic Criteria 3.1, Syndromic
Autism Reports / Total Reports
5 / 6
Rare Variants / Common Variants
13 / 1
Aliases
RIMS2, OBOE,  RAB3IP3,  RIM2
Associated Syndromes
-
Chromosome Band
8q22.3
Associated Disorders
ASD
Relevance to Autism

Biallelic variants in the RIMS2 gene were identified in seven individuals from four unrelated families presenting with syndromic congenital cone-rod synaptic disorder; five of these individuals presented with autistic behavior (Mechaussier et al., 2020). An intronic polymorphism in RIMS2 (rs2080610) had previously been shown to associate with Asperger syndrome in discovery and validation cohorts in Salyakina et al., 2010, while rare CNVs affecting RIMS2 had been identified in two Chinese ASD probands in Fan et al., 2018.

Molecular Function

The protein encoded by this gene is a presynaptic protein that interacts with RAB3, a protein important for normal neurotransmitter release. The encoded protein can also bind several other synaptic proteins, including UNC-13 homolog B, ELKS/Rab6-interacting/CAST family member 1, and synaptotagmin 1. This protein is involved in synaptic membrane exocytosis.

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Reports related to RIMS2 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association Variants in several genomic regions associated with asperger disorder Salyakina D et al. (2010) Yes -
2 Support Rare Copy Number Variations in a Chinese Cohort of Autism Spectrum Disorder Fan Y et al. (2018) Yes -
3 Primary Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement Mechaussier S et al. (2020) No Autistic behavior, stereotypy
4 Support - Woodbury-Smith M et al. (2022) Yes -
5 Support - Zhou X et al. (2022) Yes -
6 Support - More RP et al. (2023) Yes -
Rare Variants   (13)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - Unknown 30619482 Fan Y et al. (2018)
- - copy_number_loss Unknown - Unknown 30619482 Fan Y et al. (2018)
c.253C>T p.Leu85Phe stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.300T>A p.Phe100Leu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.253C>T p.Leu85Phe stop_gained De novo - Simplex 35982159 Zhou X et al. (2022)
c.503G>A p.Arg168Gln missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.328G>C p.Glu110Gln missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.833C>T p.Ser278Phe missense_variant Familial - Multiplex 36702863 More RP et al. (2023)
c.3126G>A p.Trp1042Ter stop_gained Familial Both parents - 32470375 Mechaussier S et al. (2020)
c.2884C>T p.Gln962Ter stop_gained Familial Maternal Simplex 32470375 Mechaussier S et al. (2020)
c.1595C>G p.Ser532Ter stop_gained Familial Both parents Simplex 32470375 Mechaussier S et al. (2020)
c.3508C>T p.Arg1170Ter stop_gained Familial Both parents Multiplex 32470375 Mechaussier S et al. (2020)
c.3656G>A p.Gly1219Asp splice_site_variant Familial Paternal Simplex 32470375 Mechaussier S et al. (2020)
Common Variants   (1)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.176+40118A>C - intron_variant - - - 21182207 Salyakina D et al. (2010)
SFARI Gene score
3S

Suggestive Evidence, Syndromic

Score Delta: Score remained at 3S

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

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
3S

Increased from to 3S

Krishnan Probability Score

Score 0.60888006470577

Ranking 273/25841 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 0.99999839861595

Ranking 333/18225 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 0.94937020786763

Ranking 18063/18665 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 0.41145879282755

Ranking 1329/20870 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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