Human Gene Module / Chromosome 12 / SMARCC2

SMARCC2SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily c, member 2

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
8 / 12
Rare Variants / Common Variants
21 / 0
Aliases
SMARCC2, BAF170,  CRACC2,  Rsc8
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Chromosome Band
12q13.2
Associated Disorders
EPS, ASD
Relevance to Autism

A de novo splice-site variant in this gene was identified in a simplex ASD proband (Neale et al., 2012). The protein encoded by the SMARCC2 gene interacts with the protein encoded by the high-confidence ASD gene ADNP (Mandel and Gozes, 2007).

Molecular Function

The protein encoded by this gene is a member of the SWI/SNF family of proteins, whose members display helicase and ATPase activities and which are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI and contains a predicted leucine zipper motif typical of many transcription factors.

Reports related to SMARCC2 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex. Mandel S and Gozes I (2007) No -
2 Primary Patterns and rates of exonic de novo mutations in autism spectrum disorders. Neale BM , et al. (2012) Yes -
3 Support De novo gene disruptions in children on the autistic spectrum. Iossifov I , et al. (2012) Yes -
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission. Iossifov I , et al. (2015) Yes -
5 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia. Takata A , et al. (2016) No -
6 Support High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing. Martnez F , et al. (2016) No Epilepsy/seizures
7 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
8 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
9 Support A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies. Liu Y , et al. (2018) Yes -
10 Recent Recommendation Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay. Machol K , et al. (2018) No ASD
11 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks. Ruzzo EK , et al. (2019) Yes -
12 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. Satterstrom FK , et al. (2020) Yes -
Rare Variants   (21)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - splicing_variant De novo NA - 29754769 Liu Y , et al. (2018)
- - loss_of_function_variant De novo NA - 29754769 Liu Y , et al. (2018)
c.956+1dup - frameshift_variant Unknown - - 30580808 Machol K , et al. (2018)
c.1311-3C>G - splicing_variant De novo NA - 27620904 Martnez F , et al. (2016)
c.*214_*216del - inframe_deletion De novo NA - 30580808 Machol K , et al. (2018)
c.1926+2T>C - splice_site_variant De novo NA - 30580808 Machol K , et al. (2018)
c.400A>G p.Asn134Asp missense_variant De novo NA - 30580808 Machol K , et al. (2018)
c.1826T>C p.Leu609Pro missense_variant De novo NA - 30580808 Machol K , et al. (2018)
c.1829T>C p.Leu610Pro missense_variant De novo NA - 30580808 Machol K , et al. (2018)
c.1838T>C p.Leu613Pro missense_variant De novo NA - 30580808 Machol K , et al. (2018)
c.1903T>C p.Cys635Arg missense_variant De novo NA - 30580808 Machol K , et al. (2018)
c.2915A>G p.Tyr972Cys missense_variant De novo NA - 30580808 Machol K , et al. (2018)
c.1863+1G>T - splice_site_variant De novo NA Simplex 22495311 Neale BM , et al. (2012)
c.1179+2T>A - splice_site_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.1555C>T p.Arg519Ter stop_gained De novo NA Simplex 28263302 C Yuen RK , et al. (2017)
c.1926+1G>T - splice_site_variant Unknown Not maternal - 30580808 Machol K , et al. (2018)
c.1863+1G>T - splice_site_variant De novo NA Simplex 31981491 Satterstrom FK , et al. (2020)
c.723G>A p.Trp241Ter stop_gained Familial Paternal Simplex 30580808 Machol K , et al. (2018)
c.862C>T p.Arg288Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.3372G>C p.Pro1124%3D synonymous_variant De novo NA Simplex 22542183 Iossifov I , et al. (2012)
c.2686A>G p.Met896Val missense_variant De novo NA Multi-generational 30580808 Machol K , et al. (2018)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A second de novo LoF variant in this gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), SMARCC2 was determined to be an ASD candidate gene in Yuen et al., 2017. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified SMARCC2 as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a splicing SNV. Machol et al., 2018 reported 15 unrelated individuals with variants in the SMARCC2 gene that presentedwith a neurodevelopmental syndrome characterized by developmental delay/intellectual disability, speech delay, and hypotonia; behavioral abnormalities were also frequently observed in this cohort, with one individual presenting with ASD and three others presenting with difficulties with social interactions.

Score Delta: Score remained at 2S

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.

1/1/2020
2S
icon
2S

Score remained at 2S

Description

A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A second de novo LoF variant in this gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), SMARCC2 was determined to be an ASD candidate gene in Yuen et al., 2017. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified SMARCC2 as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a splicing SNV. Machol et al., 2018 reported 15 unrelated individuals with variants in the SMARCC2 gene that presentedwith a neurodevelopmental syndrome characterized by developmental delay/intellectual disability, speech delay, and hypotonia; behavioral abnormalities were also frequently observed in this cohort, with one individual presenting with ASD and three others presenting with difficulties with social interactions.

10/1/2019
2S
icon
1

Decreased from 2S to 1

New Scoring Scheme
Description

A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A second de novo LoF variant in this gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), SMARCC2 was determined to be an ASD candidate gene in Yuen et al., 2017. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified SMARCC2 as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a splicing SNV. Machol et al., 2018 reported 15 unrelated individuals with variants in the SMARCC2 gene that presentedwith a neurodevelopmental syndrome characterized by developmental delay/intellectual disability, speech delay, and hypotonia; behavioral abnormalities were also frequently observed in this cohort, with one individual presenting with ASD and three others presenting with difficulties with social interactions.

Reports Added
[New Scoring Scheme]
7/1/2019
2S
icon
2S

Decreased from 2S to 2S

Description

A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A second de novo LoF variant in this gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), SMARCC2 was determined to be an ASD candidate gene in Yuen et al., 2017. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified SMARCC2 as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a splicing SNV. Machol et al., 2018 reported 15 unrelated individuals with variants in the SMARCC2 gene that presentedwith a neurodevelopmental syndrome characterized by developmental delay/intellectual disability, speech delay, and hypotonia; behavioral abnormalities were also frequently observed in this cohort, with one individual presenting with ASD and three others presenting with difficulties with social interactions.

1/1/2019
2
icon
2S

Decreased from 2 to 2S

Description

A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A second de novo LoF variant in this gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), SMARCC2 was determined to be an ASD candidate gene in Yuen et al., 2017. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified SMARCC2 as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a splicing SNV. Machol et al., 2018 reported 15 unrelated individuals with variants in the SMARCC2 gene that presentedwith a neurodevelopmental syndrome characterized by developmental delay/intellectual disability, speech delay, and hypotonia; behavioral abnormalities were also frequently observed in this cohort, with one individual presenting with ASD and three others presenting with difficulties with social interactions.

7/1/2018
3.3 + acc
icon
2

Decreased from 3.3 + acc to 2

Description

A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A second de novo LoF variant in this gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), SMARCC2 was determined to be an ASD candidate gene in Yuen et al., 2017. TADA-Annotations (TADA-A) analysis of whole-genome sequencing data from five studies with a total of 314 ASD-affected subjects in Liu et al., 2018 identified SMARCC2 as an ASD risk gene with a false discovery rate (FDR) < 0.3; among the de novo variants associated with this gene in ASD subjects was a loss-of-function variant and a splicing SNV.

4/1/2018
4/1/2017
3
icon
2

Decreased from 3 to 2

Description

A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A second de novo LoF variant in this gene was identified in an ASD proband from a simplex family from the ASD: Genomes to Outcome Study cohort by whole genome sequencing as part of the MSSNG initiative in Yuen et al., 2017. Based on the discovery of two de novo LoF variants in this gene in ASD probands, a probability of LoF intolerance rate (pLI) > 0.9, and higher-than-expected mutation rate (false discovery rate < 15%), SMARCC2 was determined to be an ASD candidate gene in Yuen et al., 2017.

10/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

4/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

1/1/2016
icon
3

Increased from to 3

Description

A de novo LoF variant in this gene was identified in an ASD proband from the Autism Sequencing Consortium (Neale et al., 2012). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Krishnan Probability Score

Score 0.56537772870545

Ranking 1249/25841 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 0.99999998905853

Ranking 137/18225 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
Iossifov Probability Score

Score 0.923

Ranking 119/239 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
Sanders TADA Score

Score 0.55407446642176

Ranking 575/18665 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 0.54113837789904

Ranking 278/20870 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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SFARI Gene Update

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