Human Gene Module / Chromosome 9 / SMARCA2

SMARCA2SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
12 / 30
Rare Variants / Common Variants
39 / 4
Aliases
SMARCA2, BAF190,  BRM,  NCBRS,  SNF2,  SNF2L2,  SNF2LA,  SWI2,  Sth1p,  hBRM,  hSNF2a
Associated Syndromes
Nicolaides-Baraitser syndrome, Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, DD, epilepsy/seizur, Nicolaides-Baraitser syndrome, ASD, ID
Chromosome Band
9p24.3
Associated Disorders
DD/NDD, ID, EP, EPS, ASD
Relevance to Autism

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges. Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

Molecular Function

The protein encoded by this gene is a member of the SWI/SNF family of proteins and is highly similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and 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, which is required for transcriptional activation of genes normally repressed by chromatin.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SMARCA2 (30 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Positive Association Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia Koga M , et al. (2009) No -
2 Support Nicolaides-Baraitser syndrome: Delineation of the phenotype Sousa SB , et al. (2009) No -
3 Support Nicolaides-Baraitser syndrome: two new cases with autism spectrum disorder Gana S , et al. (2010) No ASD
4 Support Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome Van Houdt JK , et al. (2012) No ID
5 Support Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome Tsurusaki Y , et al. (2012) No DD, ID
6 Primary In-Frame Deletion and Missense Mutations of the C-Terminal Helicase Domain of SMARCA2 in Three Patients with Nicolaides-Baraitser Syndrome Wolff D , et al. (2012) No ID, Epilepsy, ASD (1/3)
7 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
8 Support New SMARCA2 mutation in a patient with Nicolaides-Baraitser syndrome and myoclonic astatic epilepsy Tang S , et al. (2016) No ASD, ID, epilepsy/seizures
9 Support Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior Doan RN , et al. (2016) Yes -
10 Support A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology Vissers LE , et al. (2017) No -
11 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) No -
12 Support Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains Geisheker MR , et al. (2017) Yes -
13 Support Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients Chrot E , et al. (2017) No -
14 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
15 Support Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes Xiong J , et al. (2019) Yes ID
16 Support Variant recurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense variants Lecoquierre F , et al. (2019) No -
17 Support - Alonso-Gonzalez A et al. (2021) Yes -
18 Support - Hiraide T et al. (2021) No -
19 Support - Pan N et al. (2021) No Autistic features
20 Support - Mahjani B et al. (2021) Yes -
21 Support - Lee Y et al. (2021) No -
22 Support - Chen S et al. (2021) Yes Epilepsy/seizures
23 Support - Li D et al. (2022) Yes -
24 Support - England) (02/1) Yes -
25 Support - Levchenko O et al. (2022) No Autistic features
26 Support - Zhou X et al. (2022) Yes -
27 Support - Cirnigliaro M et al. (2023) Yes -
28 Support - Derek Chaves Lopes et al. (2023) Yes -
29 Support - Marketa Wayhelova et al. (2024) No -
30 Support - Camilla Sarli et al. () No -
Rare Variants   (39)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - Simplex 22822383 Wolff D , et al. (2012)
c.451A>T p.Ser151Cys missense_variant Unknown - - 35699097 England) (02/1)
c.1046+3462T>C - intron_variant - - Unknown 27667684 Doan RN , et al. (2016)
c.4736G>A p.Arg1579His missense_variant Unknown - - 35699097 England) (02/1)
c.3796C>T p.Arg1266Trp missense_variant Unknown - - 34968013 Li D et al. (2022)
c.2554G>A p.Glu852Lys missense_variant De novo - - 34800434 Chen S et al. (2021)
c.2564G>A p.Arg855Gln missense_variant De novo - - 34800434 Chen S et al. (2021)
c.3394G>A p.Gly1132Ser missense_variant De novo - - 34800434 Chen S et al. (2021)
c.3490G>T p.Gly1164Trp missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3721C>G p.Gln1241Glu missense_variant De novo - - 27665729 Tang S , et al. (2016)
c.2554G>A p.Glu852Lys missense_variant De novo - - 31031587 Xiong J , et al. (2019)
c.2564G>A p.Arg855Gln missense_variant De novo - - 31031587 Xiong J , et al. (2019)
c.3495G>C p.Gln1165His missense_variant De novo - - 28708303 Chrot E , et al. (2017)
c.3917G>A p.Arg1306Lys missense_variant De novo - - 28708303 Chrot E , et al. (2017)
c.3394G>A p.Gly1132Ser missense_variant De novo - - 31031587 Xiong J , et al. (2019)
c.1748C>T p.Pro583Leu missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.1679G>A p.Arg560Lys missense_variant Familial Maternal - 35699097 England) (02/1)
c.3438C>A p.Ser1146Arg missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.3485G>A p.Arg1162His missense_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.2810G>A p.Arg937His missense_variant De novo - - 27479843 Lelieveld SH et al. (2016)
c.3479C>G p.Ala1160Gly missense_variant De novo - Simplex 34706719 Lee Y et al. (2021)
c.1538G>T p.Gly513Val missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1592A>G p.Gln531Arg missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.1596G>C p.Gln532His missense_variant Unknown - - 28628100 Geisheker MR , et al. (2017)
c.3509G>C p.Arg1170Pro missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.1514G>A p.Arg505Gln missense_variant De novo - - 31036916 Lecoquierre F , et al. (2019)
c.4046G>A p.Arg1349Gln missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.3395G>A p.Gly1132Asp missense_variant De novo - Simplex 22822383 Wolff D , et al. (2012)
c.3563C>A p.Ala1188Glu missense_variant De novo - Simplex 22822383 Wolff D , et al. (2012)
c.3610T>G p.Phe1204Val missense_variant De novo - Unknown 33644862 Hiraide T et al. (2021)
c.1258C>T p.Arg420Cys missense_variant De novo - Simplex 35887114 Levchenko O et al. (2022)
c.3314G>C p.Arg1105Pro missense_variant De novo - - 37970954 Derek Chaves Lopes et al. (2023)
c.3314G>A p.Arg1105His missense_variant Familial Maternal - 28333917 Vissers LE , et al. (2017)
c.2086del p.Arg696GlyfsTer24 frameshift_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.3284G>A p.Arg1095His missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.3313C>G p.Arg1105Gly missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.3292G>C p.Gly1098Arg missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.3673G>A p.Glu1225Lys missense_variant De novo - Simplex 38321498 Marketa Wayhelova et al. (2024)
c.553C>G p.Gln185Glu missense_variant De novo (germline mosaicism) - Multiplex 34296532 Pan N et al. (2021)
Common Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
c.1936-55A>T - intron_variant - - - 19363039 Koga M , et al. (2009)
c.1935+216C>T - intron_variant - - - 19363039 Koga M , et al. (2009)
c.2884-699T>G - intron_variant - - - 19363039 Koga M , et al. (2009)
c.4638C>G p.Asp1546Glu missense_variant - - - 19363039 Koga M , et al. (2009)
SFARI Gene score
1S

High Confidence, Syndromic

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

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."

4/1/2022
S
icon
1S

Increased from S to 1S

Description

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

1/1/2021
S
icon
S

Increased from S to S

Description

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

Reports Added
[Exploring the biological role of postzygotic and germinal de novo mutations in ASD2021] [Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2019
S
icon
S

Increased from S to S

New Scoring Scheme
Description

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

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

Increased from S to S

Description

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

Reports Added
[Variantrecurrence in neurodevelopmental disorders: the use of publicly available genomic data identifies clinically relevant pathogenic missense v...2019]
4/1/2019
S
icon
S

Increased from S to S

Description

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

Reports Added
[Neurological Diseases With Autism Spectrum Disorder: Role of ASD Risk Genes.2019]
10/1/2017
S
icon
S

Increased from S to S

Description

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
7/1/2017
S
icon
S

Increased from S to S

Description

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

Reports Added
[Hotspots of missense mutation identify neurodevelopmental disorder genes and functional domains.2017] [Using medical exome sequencing to identify the causes of neurodevelopmental disorders: experience of two clinical units and 216 patients.2017]
4/1/2017
S
icon
S

Increased from S to S

Description

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

Reports Added
[In-Frame Deletion and Missense Mutations of the C-Terminal Helicase Domain of SMARCA2 in Three Patients with Nicolaides-Baraitser Syndrome.2012] [Nicolaides-Baraitser syndrome: two new cases with autism spectrum disorder.2010] [Involvement of SMARCA2/BRM in the SWI/SNF chromatin-remodeling complex in schizophrenia.2009] [Heterozygous missense mutations in SMARCA2 cause Nicolaides-Baraitser syndrome.2012] [Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome.2012] [Nicolaides-Baraitser syndrome: Delineation of the phenotype.2009] [Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016] [New SMARCA2 mutation in a patient with Nicolaides-Baraitser syndrome and myoclonic astatic epilepsy.2016] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016] [A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology.2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
10/1/2016
S
icon
S

Increased from S to S

Description

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

Reports Added
[New SMARCA2 mutation in a patient with Nicolaides-Baraitser syndrome and myoclonic astatic epilepsy.2016] [Mutations in Human Accelerated Regions Disrupt Cognition and Social Behavior.2016]
7/1/2016
S
icon
S

Increased from S to S

Description

Defects in SMARCA2 are the cause of Nicolaides-Baraitser syndrome (NCBRS) [MIM:601358], a rare disorder characterized by severe mental retardation with absent or limited speech, seizures, short stature, sparse hair, typical facial characteristics, brachydactyly, prominent finger joints and broad distal phalanges (Van Houdt et al., 2012). Some individuals with NCBRS have also been formally diagnosed with ASD or have displayed autistic traits (Sousa et al., 2009; Gana et al., 2011; Wolff et al., 2012).

Reports Added
[Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability2016]
Krishnan Probability Score

Score 0.56894063376042

Ranking 1077/25841 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 0.99999826353949

Ranking 343/18225 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 0.86464562775571

Ranking 4050/18665 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 0.25081444653338

Ranking 3475/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
Actl6b actin-like 6B Mouse Protein Binding 83766 Q99MR0
RELB Transcription factor RelB Human Protein Binding 5971 Q01201
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