9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Position:

• chr9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003070.5(SMARCA2):​c.702_707dup​(p.Gln237_Gln238dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00268 in 1,596,150 control chromosomes in the GnomAD database, including 26 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q222Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0099 (25 hom., cov: 26)
  • Exomes 𝑓: 0.0019 (1 hom.)
• Consequence: SMARCA2 NM_003070.5 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.00

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 -16 ACMG points.

• BP6: Variant 9-2039776-A-ACAGCAG is Benign according to our data. Variant chr9-2039776-A-ACAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 436800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00987 (1486/150520) while in subpopulation AFR AF= 0.0304 (1244/40896). AF 95% confidence interval is 0.029. There are 25 homozygotes in gnomad4. There are 689 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1486 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA2	NM_003070.5	c.702_707dup	p.Gln237_Gln238dup	inframe_insertion	4/34	ENST00000349721.8
SMARCA2	NM_001289396.1	c.702_707dup	p.Gln237_Gln238dup	inframe_insertion	4/34
SMARCA2	NM_001289397.2	c.702_707dup	p.Gln237_Gln238dup	inframe_insertion	4/33
SMARCA2	NM_139045.4	c.702_707dup	p.Gln237_Gln238dup	inframe_insertion	4/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA2	ENST00000349721.8	c.702_707dup	p.Gln237_Gln238dup	inframe_insertion	4/34	5	NM_003070.5	P2

Frequencies

GnomAD3 genomes AF: 0.00987 AC: 1484 AN: 150420 Hom.: 25 Cov.: 26

Gnomad AFR AF: 0.0305

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00430

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000846

Gnomad FIN AF: 0.0000965

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000888

Gnomad OTH AF: 0.0121

GnomAD4 exome AF: 0.00194 AC: 2798 AN: 1445630 Hom.: 1 Cov.: 28 AF XY: 0.00186 AC XY: 1337 AN XY: 718444

Gnomad4 AFR exome AF: 0.0310

Gnomad4 AMR exome AF: 0.00255

Gnomad4 ASJ exome AF: 0.0198

Gnomad4 EAS exome AF: 0.00107

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.000193

Gnomad4 NFE exome AF: 0.000671

Gnomad4 OTH exome AF: 0.00419

GnomAD4 genome AF: 0.00987 AC: 1486 AN: 150520 Hom.: 25 Cov.: 26 AF XY: 0.00938 AC XY: 689 AN XY: 73480

Gnomad4 AFR AF: 0.0304

Gnomad4 AMR AF: 0.00430

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.000197

Gnomad4 SAS AF: 0.000849

Gnomad4 FIN AF: 0.0000965

Gnomad4 NFE AF: 0.000888

Gnomad4 OTH AF: 0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 09, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 12, 2015	- -

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Sep 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2020	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2019

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113070757; hg19: chr9-2039776;