9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Position:

• chr9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

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.693_707dup​(p.Gln234_Gln238dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000126 in 150,532 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. Q222Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000071 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA2 NM_003070.5 inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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-ACAGCAGCAGCAGCAG is Benign according to our data. Variant chr9-2039776-A-ACAGCAGCAGCAGCAG is described in ClinVar as [Likely_benign]. Clinvar id is 1209185.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 = 0.000126 (19/150532) while in subpopulation SAS AF= 0.000637 (3/4712). AF 95% confidence interval is 0.000173. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.693_707dup	p.Gln234_Gln238dup	inframe_insertion	4/34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.1	c.693_707dup	p.Gln234_Gln238dup	inframe_insertion	4/34		NP_001276325.1
SMARCA2	NM_001289397.2	c.693_707dup	p.Gln234_Gln238dup	inframe_insertion	4/33		NP_001276326.1
SMARCA2	NM_139045.4	c.693_707dup	p.Gln234_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.693_707dup	p.Gln234_Gln238dup	inframe_insertion	4/34	5	NM_003070.5	ENSP00000265773	P2

Frequencies

GnomAD3 genomes AF: 0.000126 AC: 19 AN: 150432 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000662

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000635

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000888

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000705 AC: 102 AN: 1445802 Hom.: 0 Cov.: 28 AF XY: 0.0000905 AC XY: 65 AN XY: 718558

Gnomad4 AFR exome AF: 0.000244

Gnomad4 AMR exome AF: 0.0000468

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.0000260

Gnomad4 SAS exome AF: 0.000636

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.0000290

Gnomad4 OTH exome AF: 0.0000335

GnomAD4 genome AF: 0.000126 AC: 19 AN: 150532 Hom.: 0 Cov.: 26 AF XY: 0.000163 AC XY: 12 AN XY: 73486

Gnomad4 AFR AF: 0.000220

Gnomad4 AMR AF: 0.0000661

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000637

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000888

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2020

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 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;