rs13288443

chr9-2073292-A-G

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.1827A>G(p.Pro609=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,613,946 control chromosomes in the GnomAD database, including 11,436 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1215 hom., cov: 32)
  • Exomes 𝑓: 0.12 (10221 hom.)
• Consequence: SMARCA2 NM_003070.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.402

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=-0.47).
• BP6: Variant 9-2073292-A-G is Benign according to our data. Variant chr9-2073292-A-G is described in ClinVar as [Benign]. Clinvar id is 126345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2073292-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.402 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA2	NM_003070.5	c.1827A>G	p.Pro609=	synonymous_variant	11/34	ENST00000349721.8
SMARCA2	NM_001289396.1	c.1827A>G	p.Pro609=	synonymous_variant	11/34
SMARCA2	NM_139045.4	c.1827A>G	p.Pro609=	synonymous_variant	11/33
SMARCA2	NM_001289397.2	c.1827A>G	p.Pro609=	synonymous_variant	11/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA2	ENST00000349721.8	c.1827A>G	p.Pro609=	synonymous_variant	11/34	5	NM_003070.5	P2

Frequencies

GnomAD3 genomes AF: 0.120 AC: 18313 AN: 152094 Hom.: 1215 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.0706

Gnomad EAS AF: 0.0497

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.148

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.120 AC: 30078 AN: 251364 Hom.: 1966 AF XY: 0.119 AC XY: 16212 AN XY: 135870

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.0714

Gnomad EAS exome AF: 0.0509

Gnomad SAS exome AF: 0.136

Gnomad FIN exome AF: 0.148

Gnomad NFE exome AF: 0.113

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.116 AC: 169809 AN: 1461734 Hom.: 10221 Cov.: 32 AF XY: 0.117 AC XY: 85006 AN XY: 727168

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.154

Gnomad4 ASJ exome AF: 0.0723

Gnomad4 EAS exome AF: 0.0498

Gnomad4 SAS exome AF: 0.139

Gnomad4 FIN exome AF: 0.149

Gnomad4 NFE exome AF: 0.115

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.120 AC: 18326 AN: 152212 Hom.: 1215 Cov.: 32 AF XY: 0.123 AC XY: 9153 AN XY: 74422

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.154

Gnomad4 ASJ AF: 0.0706

Gnomad4 EAS AF: 0.0498

Gnomad4 SAS AF: 0.125

Gnomad4 FIN AF: 0.148

Gnomad4 NFE AF: 0.112

Gnomad4 OTH AF: 0.103

Alfa AF: 0.112 Hom.: 1376

Bravo AF: 0.120

Asia WGS AF: 0.0840 AC: 295 AN: 3478

EpiCase AF: 0.104

EpiControl AF: 0.103

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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2013

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 02, 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 12, 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	-0.47
Cadd	Benign	6.3
Dann	Benign	0.72

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: rs13288443; hg19: chr9-2073292; COSMIC: COSV100570667; COSMIC: COSV100570667;