SMARCA2

Chr 9

SWI/SNF related BAF chromatin remodeling complex subunit ATPase 2

Also known as: BAF190, BIS, BRM, NCBRS, SAMRCA2, SNF2, SNF2L2, SNF2LA

NCBI Gene: 6595 ENSG00000080503 UniProt: P51531

The protein is an ATPase subunit of the SWI/SNF chromatin remodeling complex that regulates gene transcription by altering chromatin structure around target genes. Loss-of-function mutations cause autosomal dominant Nicolaides-Baraitser syndrome and Blepharophimosis-impaired intellectual development syndrome. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the pathogenic mechanism.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, which contains a trinucleotide repeat (CAG) length polymorphism. [provided by RefSeq, Jan 2014]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.20

Clinical Summary— SMARCA2

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Gene-Disease Validity (ClinGen)

intellectual disability-sparse hair-brachydactyly syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 7.69

OE 0.12 (0.08–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

5.05Z-score

OE missense 0.53 (0.49–0.57)

476 obs / 903.5 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.12 (0.08–0.20)

0≤0.351.4

Missense OE?0.53 (0.49–0.57)

0≤0.61.4

Synonymous OE?1.29

0≤1.21.6

LoF obs/exp: 11 / 89.6Missense obs/exp: 476 / 903.5Syn Z: -4.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSMARCA2-related Nicolaides-Baraitser syndromeOTHERAD

This gene — mechanism propensity

0.4488th %ile

GOF

0.4184th %ile

LOF

0.69top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.20

DN1 literature citation

Literature Evidence

DNDominant negative effects of SMARCA2 mutations may contribute to Nicolaides-Baraitser syndrome. We conclude that their features better resemble Coffin-Siris syndrome, rather than Nicolaides-Baraitser syndrome and that these features likely arise from SMARCA2 over-dosage.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References