9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAG

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.699_707del(p.Gln236_Gln238del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.004 in 1,596,338 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q223Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (4 hom., cov: 26)
  • Exomes 𝑓: 0.0039 (7 hom.)
• Consequence: SMARCA2 NM_003070.5 inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.16

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-ACAGCAGCAG-A is Benign according to our data. Variant chr9-2039776-ACAGCAGCAG-A is described in ClinVar as [Likely_benign]. Clinvar id is 212231.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2039776-ACAGCAGCAG-A is described in Lovd as [Likely_benign]. Variant chr9-2039776-ACAGCAGCAG-A is described in Lovd as [Likely_benign]. Variant chr9-2039776-ACAGCAGCAG-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00529 (797/150528) while in subpopulation AFR AF= 0.0105 (429/40904). AF 95% confidence interval is 0.00967. There are 4 homozygotes in gnomad4. There are 381 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd at 798 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA2	NM_003070.5	c.699_707del	p.Gln236_Gln238del	inframe_deletion	4/34	ENST00000349721.8
SMARCA2	NM_001289396.1	c.699_707del	p.Gln236_Gln238del	inframe_deletion	4/34
SMARCA2	NM_001289397.2	c.699_707del	p.Gln236_Gln238del	inframe_deletion	4/33
SMARCA2	NM_139045.4	c.699_707del	p.Gln236_Gln238del	inframe_deletion	4/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA2	ENST00000349721.8	c.699_707del	p.Gln236_Gln238del	inframe_deletion	4/34	5	NM_003070.5	P2

Frequencies

GnomAD3 genomes AF: 0.00530 AC: 798 AN: 150428 Hom.: 4 Cov.: 26

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00430

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00334

Gnomad SAS AF: 0.00592

Gnomad FIN AF: 0.000289

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.00360

Gnomad OTH AF: 0.00532

GnomAD4 exome AF: 0.00386 AC: 5586 AN: 1445810 Hom.: 7 AF XY: 0.00391 AC XY: 2813 AN XY: 718568

Gnomad4 AFR exome AF: 0.00994

Gnomad4 AMR exome AF: 0.00417

Gnomad4 ASJ exome AF: 0.000696

Gnomad4 EAS exome AF: 0.00466

Gnomad4 SAS exome AF: 0.00674

Gnomad4 FIN exome AF: 0.000890

Gnomad4 NFE exome AF: 0.00363

Gnomad4 OTH exome AF: 0.00348

GnomAD4 genome AF: 0.00529 AC: 797 AN: 150528 Hom.: 4 Cov.: 26 AF XY: 0.00518 AC XY: 381 AN XY: 73486

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.00430

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00335

Gnomad4 SAS AF: 0.00594

Gnomad4 FIN AF: 0.000289

Gnomad4 NFE AF: 0.00358

Gnomad4 OTH AF: 0.00526

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jul 07, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	SMARCA2: BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 31, 2019

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2021

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. -

Nicolaides-Baraitser syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jun 06, 2023

- -

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;