rs6601

chr9-2116037-G-Achr9-2116037-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003070.5(SMARCA2):c.3672G>A(p.Glu1224=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,612,202 control chromosomes in the GnomAD database, including 22,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (7917 hom., cov: 32)
  • Exomes 𝑓: 0.12 (14711 hom.)
• Consequence: SMARCA2 NM_003070.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.191

Genes affected

SMARCA2 (HGNC:11098): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2) 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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 9-2116037-G-A is Benign according to our data. Variant chr9-2116037-G-A is described in ClinVar as [Benign]. Clinvar id is 126346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.191 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA2	NM_003070.5	c.3672G>A	p.Glu1224=	synonymous_variant	25/34	ENST00000349721.8
SMARCA2	NM_001289396.1	c.3672G>A	p.Glu1224=	synonymous_variant	25/34
SMARCA2	NM_139045.4	c.3672G>A	p.Glu1224=	synonymous_variant	25/33
SMARCA2	NM_001289397.2	c.3498G>A	p.Glu1166=	synonymous_variant	25/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA2	ENST00000349721.8	c.3672G>A	p.Glu1224=	synonymous_variant	25/34	5	NM_003070.5	P2

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35534 AN: 151964 Hom.: 7872 Cov.: 32

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.0194

Gnomad SAS AF: 0.0926

Gnomad FIN AF: 0.0873

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.179

GnomAD3 exomes AF: 0.123 AC: 30639 AN: 249844 Hom.: 4060 AF XY: 0.115 AC XY: 15499 AN XY: 135106

Gnomad AFR exome AF: 0.606

Gnomad AMR exome AF: 0.0649

Gnomad ASJ exome AF: 0.0919

Gnomad EAS exome AF: 0.0156

Gnomad SAS exome AF: 0.0997

Gnomad FIN exome AF: 0.0898

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.115 AC: 168002 AN: 1460120 Hom.: 14711 Cov.: 30 AF XY: 0.113 AC XY: 81859 AN XY: 726386

Gnomad4 AFR exome AF: 0.617

Gnomad4 AMR exome AF: 0.0715

Gnomad4 ASJ exome AF: 0.0883

Gnomad4 EAS exome AF: 0.0300

Gnomad4 SAS exome AF: 0.0973

Gnomad4 FIN exome AF: 0.0916

Gnomad4 NFE exome AF: 0.107

Gnomad4 OTH exome AF: 0.133

GnomAD4 genome AF: 0.234 AC: 35634 AN: 152082 Hom.: 7917 Cov.: 32 AF XY: 0.227 AC XY: 16874 AN XY: 74362

Gnomad4 AFR AF: 0.593

Gnomad4 AMR AF: 0.112

Gnomad4 ASJ AF: 0.0798

Gnomad4 EAS AF: 0.0195

Gnomad4 SAS AF: 0.0931

Gnomad4 FIN AF: 0.0873

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.177

Alfa AF: 0.136 Hom.: 2443

Bravo AF: 0.253

Asia WGS AF: 0.0950 AC: 330 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.106

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 13, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Nicolaides-Baraitser syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.74
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6601; hg19: chr9-2116037; COSMIC: COSV61807520;