9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Position:

• chr9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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.696_707dupGCAGCAGCAGCA​(p.Gln233_Gln236dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000983 in 150,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q236Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00098 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00070 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA2 NM_003070.5 disruptive_inframe_insertion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• 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]

SMARCA2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 9-2039776-A-ACAGCAGCAGCAG is Benign according to our data. Variant chr9-2039776-A-ACAGCAGCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 588473.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 = 0.000983 (148/150530) while in subpopulation SAS AF= 0.00446 (21/4712). AF 95% confidence interval is 0.00299. There are 0 homozygotes in gnomad4. There are 83 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 148 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.696_707dupGCAGCAGCAGCA	p.Gln233_Gln236dup	disruptive_inframe_insertion	4/34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.1	c.696_707dupGCAGCAGCAGCA	p.Gln233_Gln236dup	disruptive_inframe_insertion	4/34		NP_001276325.1
SMARCA2	NM_139045.4	c.696_707dupGCAGCAGCAGCA	p.Gln233_Gln236dup	disruptive_inframe_insertion	4/33		NP_620614.2
SMARCA2	NM_001289397.2	c.696_707dupGCAGCAGCAGCA	p.Gln233_Gln236dup	disruptive_inframe_insertion	4/33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.696_707dupGCAGCAGCAGCA	p.Gln233_Gln236dup	disruptive_inframe_insertion	4/34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes AF: 0.000990 AC: 149 AN: 150430 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00444

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000666

Gnomad OTH AF: 0.000484

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000702 AC: 1015 AN: 1445598 Hom.: 1 Cov.: 28 AF XY: 0.000767 AC XY: 551 AN XY: 718472

Gnomad4 AFR exome AF: 0.00162

Gnomad4 AMR exome AF: 0.000187

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000520

Gnomad4 SAS exome AF: 0.00292

Gnomad4 FIN exome AF: 0.0000967

Gnomad4 NFE exome AF: 0.000602

Gnomad4 OTH exome AF: 0.000553

GnomAD4 genome AF: 0.000983 AC: 148 AN: 150530 Hom.: 0 Cov.: 26 AF XY: 0.00113 AC XY: 83 AN XY: 73484

Gnomad4 AFR AF: 0.00193

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00446

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000666

Gnomad4 OTH AF: 0.000478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SMARCA2: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 20, 2018

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;