9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Position:

• chr9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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_707dup​(p.Gln236_Gln238dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 150,526 control chromosomes in the GnomAD database, including 19 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 0.010 (19 hom., cov: 26)
  • Exomes 𝑓: 0.0057 (9 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA2 NM_003070.5 inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• 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-ACAGCAGCAG is Benign according to our data. Variant chr9-2039776-A-ACAGCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 587963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0104 (1572/150526) while in subpopulation SAS AF= 0.0374 (176/4712). AF 95% confidence interval is 0.0328. There are 19 homozygotes in gnomad4. There are 752 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1572 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.699_707dup	p.Gln236_Gln238dup	inframe_insertion	4/34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.1	c.699_707dup	p.Gln236_Gln238dup	inframe_insertion	4/34		NP_001276325.1
SMARCA2	NM_001289397.2	c.699_707dup	p.Gln236_Gln238dup	inframe_insertion	4/33		NP_001276326.1
SMARCA2	NM_139045.4	c.699_707dup	p.Gln236_Gln238dup	inframe_insertion	4/33		NP_620614.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.699_707dup	p.Gln236_Gln238dup	inframe_insertion	4/34	5	NM_003070.5	ENSP00000265773	P2

Frequencies

GnomAD3 genomes AF: 0.0104 AC: 1570 AN: 150426 Hom.: 19 Cov.: 26

Gnomad AFR AF: 0.0258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00463

Gnomad ASJ AF: 0.00404

Gnomad EAS AF: 0.000589

Gnomad SAS AF: 0.0376

Gnomad FIN AF: 0.000289

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00348

Gnomad OTH AF: 0.00484

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00568 AC: 8208 AN: 1445438 Hom.: 9 Cov.: 28 AF XY: 0.00632 AC XY: 4542 AN XY: 718384

Gnomad4 AFR exome AF: 0.0273

Gnomad4 AMR exome AF: 0.00487

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.000520

Gnomad4 SAS exome AF: 0.0297

Gnomad4 FIN exome AF: 0.000677

Gnomad4 NFE exome AF: 0.00363

Gnomad4 OTH exome AF: 0.00685

GnomAD4 genome AF: 0.0104 AC: 1572 AN: 150526 Hom.: 19 Cov.: 26 AF XY: 0.0102 AC XY: 752 AN XY: 73486

Gnomad4 AFR AF: 0.0259

Gnomad4 AMR AF: 0.00463

Gnomad4 ASJ AF: 0.00404

Gnomad4 EAS AF: 0.000590

Gnomad4 SAS AF: 0.0374

Gnomad4 FIN AF: 0.000289

Gnomad4 NFE AF: 0.00348

Gnomad4 OTH AF: 0.00478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

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	GeneDx	May 17, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SMARCA2: BS1, BS2 -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

-

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 14, 2017

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;C5443984:Blepharophimosis-impaired intellectual development syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Nov 17, 2021

- -

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;