9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAG

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_003070.5(SMARCA2):c.696_707del(p.Gln235_Gln238del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,596,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q223Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 26)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: SMARCA2 NM_003070.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.94

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 -9 ACMG points.

• BP6: Variant 9-2039776-ACAGCAGCAGCAG-A is Benign according to our data. Variant chr9-2039776-ACAGCAGCAGCAG-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 588716.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3}. Variant chr9-2039776-ACAGCAGCAGCAG-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000299 (45/150532) while in subpopulation SAS AF= 0.00106 (5/4712). AF 95% confidence interval is 0.000418. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 26. This position pass quality control queck.
• BS2: High AC in GnomAd at 45 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA2	NM_003070.5	c.696_707del	p.Gln235_Gln238del	inframe_deletion	4/34	ENST00000349721.8
SMARCA2	NM_001289396.1	c.696_707del	p.Gln235_Gln238del	inframe_deletion	4/34
SMARCA2	NM_001289397.2	c.696_707del	p.Gln235_Gln238del	inframe_deletion	4/33
SMARCA2	NM_139045.4	c.696_707del	p.Gln235_Gln238del	inframe_deletion	4/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA2	ENST00000349721.8	c.696_707del	p.Gln235_Gln238del	inframe_deletion	4/34	5	NM_003070.5	P2

Frequencies

GnomAD3 genomes AF: 0.000299 AC: 45 AN: 150432 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000539

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000785

Gnomad SAS AF: 0.00106

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000133

Gnomad OTH AF: 0.000484

GnomAD4 exome AF: 0.000181 AC: 261 AN: 1445808 Hom.: 0 AF XY: 0.000207 AC XY: 149 AN XY: 718564

Gnomad4 AFR exome AF: 0.000641

Gnomad4 AMR exome AF: 0.000258

Gnomad4 ASJ exome AF: 0.0000387

Gnomad4 EAS exome AF: 0.00120

Gnomad4 SAS exome AF: 0.000565

Gnomad4 FIN exome AF: 0.0000193

Gnomad4 NFE exome AF: 0.0000951

Gnomad4 OTH exome AF: 0.000318

GnomAD4 genome AF: 0.000299 AC: 45 AN: 150532 Hom.: 0 Cov.: 26 AF XY: 0.000313 AC XY: 23 AN XY: 73486

Gnomad4 AFR AF: 0.000538

Gnomad4 AMR AF: 0.000264

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000787

Gnomad4 SAS AF: 0.00106

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000133

Gnomad4 OTH AF: 0.000478

Bravo AF: 0.000264

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with SMARCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.696_707del, results in the deletion of 4 amino acid(s) of the SMARCA2 protein (p.Gln235_Gln238del), but otherwise preserves the integrity of the reading frame. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	SMARCA2: BS1 -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 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. -

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;