Human Gene Module / Chromosome 12 / SMARCC2

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

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
11 / 20
Rare Variants / Common Variants
83 / 0
EAGLE Score
10
Moderate Learn More
Aliases
SMARCC2, BAF170,  CRACC2,  Rsc8
Associated Syndromes
-
Chromosome Band
12q13.2
Associated Disorders
DD/NDD, ASD, EPS, ID
Genetic Category
Rare Single Gene Mutation, Syndromic, Functional
Relevance to Autism

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 presented with 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. A de novo protein-truncating variant in SMARCC2 was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified SMARCC2 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). Three additional de novo loss-of-function variants in the SMARCC2 gene were reported in ASD probands from the SPARK cohort in Zhou et al., 2022; a two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in this report identified SMARCC2 as a gene reaching exome-wide significance (P < 2.5E-06).. 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.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SMARCC2 (20 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 Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
9 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
10 Support A Statistical Framework for Mapping Risk Genes from De Novo Mutations in Whole-Genome-Sequencing Studies Liu Y , et al. (2018) Yes -
11 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
12 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
13 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
14 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes DD, ID
15 Support - England) (02/1) Yes -
16 Recent Recommendation - Zhou X et al. (2022) Yes -
17 Support - Balasar et al. (2023) No -
18 Recent Recommendation - Elisabeth Bosch et al. (2023) No ASD or autistic behavior, ADHD, epilepsy/seizures
19 Support - Tamam Khalaf et al. (2024) No -
20 Support - Axel Schmidt et al. (2024) No Autistic behavior
Rare Variants   (83)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - splicing_variant De novo - - 29754769 Liu Y , et al. (2018)
- - loss_of_function_variant De novo - - 29754769 Liu Y , et al. (2018)
c.412T>C p.Ser138Pro missense_variant Unknown - - 35699097 England) (02/1)
c.415C>T p.Arg139Ter stop_gained De novo - - 33004838 Wang T et al. (2020)
c.1744-1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1996T>C p.Cys666Arg missense_variant De novo - - 28135719 et al. (2017)
c.2779A>G p.Met927Val missense_variant De novo - - 28135719 et al. (2017)
c.1748C>A p.Thr583Asn missense_variant Unknown - - 35699097 England) (02/1)
c.2353A>T p.Ser785Cys missense_variant Unknown - - 35699097 England) (02/1)
c.1420C>T p.Arg474Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1537C>T p.Gln513Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.1537C>T p.Gln513Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.956+1dup - frameshift_variant Unknown - - 30580808 Machol K , et al. (2018)
c.3305C>T p.Pro1102Leu missense_variant Unknown - - 35699097 England) (02/1)
c.3419C>T p.Ala1140Val missense_variant Unknown - - 35699097 England) (02/1)
- - copy_number_loss De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.*214_*216del - inframe_deletion De novo - - 30580808 Machol K , et al. (2018)
c.1926+2T>C - splice_site_variant De novo - - 30580808 Machol K , et al. (2018)
c.1570G>A p.Gly524Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1825C>T p.Arg609Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1874C>T p.Ala625Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1982G>A p.Arg661His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1311-3C>G - splice_region_variant De novo - - 27620904 Martnez F , et al. (2016)
c.400A>G p.Asn134Asp missense_variant De novo - - 30580808 Machol K , et al. (2018)
c.862C>T p.Arg288Ter stop_gained Familial Paternal - 33004838 Wang T et al. (2020)
c.1826T>C p.Leu609Pro missense_variant De novo - - 30580808 Machol K , et al. (2018)
c.1829T>C p.Leu610Pro missense_variant De novo - - 30580808 Machol K , et al. (2018)
c.1838T>C p.Leu613Pro missense_variant De novo - - 30580808 Machol K , et al. (2018)
c.1903T>C p.Cys635Arg missense_variant De novo - - 30580808 Machol K , et al. (2018)
c.2915A>G p.Tyr972Cys missense_variant De novo - - 30580808 Machol K , et al. (2018)
c.326dup p.Tyr109Ter stop_gained Unknown - - 37551667 Elisabeth Bosch et al. (2023)
c.1187A>G p.Asp396Gly missense_variant Familial Paternal - 35699097 England) (02/1)
c.2446G>A p.Glu816Lys missense_variant Familial Maternal - 35699097 England) (02/1)
c.1863+1G>T - splice_site_variant De novo - Simplex 22495311 Neale BM , et al. (2012)
c.2095_2097del p.Gln699del inframe_deletion De novo - - 35982159 Zhou X et al. (2022)
c.1555C>T p.Arg519Ter stop_gained De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.385A>G p.Lys129Glu missense_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.1179+2T>A - splice_site_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.3625C>T p.Gln1209Ter missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.230C>T p.Pro77Leu missense_variant De novo - - 37551667 Elisabeth Bosch et al. (2023)
c.845del p.Asn282ThrfsTer58 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.2921dup p.Met975AspfsTer68 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.2399A>G p.Lys800Arg missense_variant Unknown - Simplex 37524782 Balasar et al. (2023)
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 - Simplex 31981491 Satterstrom FK et al. (2020)
c.3222del p.Gly1075AspfsTer17 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.3243G>A p.Pro1081%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.574C>T p.Arg192Ter stop_gained De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.805C>T p.Arg269Ter stop_gained De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.805C>T p.Arg269Ter stop_gained Unknown - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.1311-1G>A - splice_site_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.317+2T>A - splice_site_variant Familial Maternal - 37551667 Elisabeth Bosch et al. (2023)
c.327C>G p.Tyr109Ter stop_gained Familial Maternal - 37551667 Elisabeth Bosch et al. (2023)
c.723G>A p.Trp241Ter stop_gained Familial Paternal Simplex 30580808 Machol K , et al. (2018)
c.3372G>C p.Pro1124= synonymous_variant De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.1094_1097del p.Lys365ThrfsTer12 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.114_115insTATA p.Ile39TyrfsTer5 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.230C>T p.Pro77Leu missense_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.862C>T p.Arg288Ter stop_gained Familial Paternal Multiplex 31398340 Ruzzo EK , et al. (2019)
c.743T>C p.Phe248Ser missense_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.640A>G p.Thr214Ala missense_variant Unknown - Unknown 37551667 Elisabeth Bosch et al. (2023)
c.1889G>A p.Arg630His missense_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.1919T>C p.Leu640Pro missense_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.2602G>C p.Glu868Gln missense_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.2732A>G p.Glu911Gly missense_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.2771A>G p.Glu924Gly missense_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.3617C>T p.Ala1206Val missense_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.1327C>T p.Arg443Trp missense_variant Familial Maternal - 37551667 Elisabeth Bosch et al. (2023)
c.2536_2537delinsTCC p.Gly846SerfsTer8 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.327C>G p.Tyr109Ter stop_gained Familial Paternal Simplex 37551667 Elisabeth Bosch et al. (2023)
c.574C>T p.Arg192Ter stop_gained Familial Paternal Simplex 37551667 Elisabeth Bosch et al. (2023)
c.1835T>C p.Met612Thr splice_site_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.2152C>T p.Arg718Ter stop_gained Familial Maternal Simplex 37551667 Elisabeth Bosch et al. (2023)
c.2686A>G p.Met896Val missense_variant De novo - Multi-generational 30580808 Machol K , et al. (2018)
c.1827C>G p.Arg609%3D splice_region_variant De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.3097dup p.Ala1033GlyfsTer10 frameshift_variant Unknown - Unknown 37551667 Elisabeth Bosch et al. (2023)
c.2790G>T p.Leu930Phe missense_variant Unknown Not maternal Simplex 37551667 Elisabeth Bosch et al. (2023)
c.1849_1854del p.Asn617_Val618del inframe_deletion De novo - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.3135_3139dup p.Ala1047GlyfsTer47 frameshift_variant Unknown - Simplex 37551667 Elisabeth Bosch et al. (2023)
c.3129del p.Ile1044LeufsTer48 frameshift_variant Familial Maternal Simplex 37551667 Elisabeth Bosch et al. (2023)
c.3129del p.Ile1044LeufsTer48 frameshift_variant Familial Maternal Multiplex 37551667 Elisabeth Bosch et al. (2023)
c.3279del p.Ala1095GlnfsTer126 frameshift_variant Unknown Not maternal Multiplex 37551667 Elisabeth Bosch et al. (2023)
c.3129del p.Ile1044LeufsTer48 frameshift_variant Familial Maternal Multiplex (monozygotic twins) 35699097 England) (02/1)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

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 1S

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.

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."

10/1/2020
1
icon
1

Score remained at 1

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
[Prevalence and architecture of de novo mutations in developmental disorders2017] [Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
1/1/2020
1
icon
1

Score remained at 1

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
[Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020]
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.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
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.

Reports Added
[Expanding the Spectrum of BAF-Related Disorders: De Novo Variants in SMARCC2 Cause a Syndrome with Intellectual Disability and Developmental Delay.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.

Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex.2007] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo gene disruptions in children on the autistic spectrum.2012] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016] [High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
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).

Reports Added
[High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
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).

Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex.2007] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo gene disruptions in children on the autistic spectrum.2012] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016]
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).

Reports Added
[Patterns and rates of exonic de novo mutations in autism spectrum disorders.2012] [Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex.2007] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
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.
Original Source
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
Original Source
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
Original Source
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).
Original Source
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.
Original Source
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