NM_003070.5:c.693_707delGCAGCAGCAGCAGCA

Variant names:

• chr9-2039776-ACAGCAGCAGCAGCAG-A
• rs113070757
• NM_003070.5:c.693_707delGCAGCAGCAGCAGCA

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3 BP6_Very_Strong BS1 BS2

The NM_003070.5(SMARCA2):​c.693_707delGCAGCAGCAGCAGCA​(p.Gln232_Gln236del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00351 in 150,530 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Q231Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0047 (12 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA2 NM_003070.5 disruptive_inframe_deletion
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.94
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• intellectual disability-sparse hair-brachydactyly syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• blepharophimosis-impaired intellectual development syndrome

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003070.5
• BP6: Variant 9-2039776-ACAGCAGCAGCAGCAG-A is Benign according to our data. Variant chr9-2039776-ACAGCAGCAGCAGCAG-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212230.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00351 (528/150530) while in subpopulation NFE AF = 0.00491 (332/67584). AF 95% confidence interval is 0.00448. There are 0 homozygotes in GnomAd4. There are 231 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 528 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003070.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA2	NM_003070.5	MANE Select	c.693_707delGCAGCAGCAGCAGCA	p.Gln232_Gln236del	disruptive_inframe_deletion	Exon 4 of 34	NP_003061.3
	SMARCA2	NM_001289396.2		c.693_707delGCAGCAGCAGCAGCA	p.Gln232_Gln236del	disruptive_inframe_deletion	Exon 4 of 34	NP_001276325.1	P51531-1
	SMARCA2	NM_139045.4		c.693_707delGCAGCAGCAGCAGCA	p.Gln232_Gln236del	disruptive_inframe_deletion	Exon 4 of 33	NP_620614.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA2	ENST00000349721.8	TSL:5 MANE Select	c.693_707delGCAGCAGCAGCAGCA	p.Gln232_Gln236del	disruptive_inframe_deletion	Exon 4 of 34	ENSP00000265773.5	P51531-1
	SMARCA2	ENST00000382203.5	TSL:1	c.693_707delGCAGCAGCAGCAGCA	p.Gln232_Gln236del	disruptive_inframe_deletion	Exon 4 of 34	ENSP00000371638.1	P51531-1
	SMARCA2	ENST00000450198.6	TSL:1	c.693_707delGCAGCAGCAGCAGCA	p.Gln232_Gln236del	disruptive_inframe_deletion	Exon 4 of 33	ENSP00000392081.2	F6VDE0

Frequencies

GnomAD3 genomes AF: 0.00351 AC: 528 AN: 150430 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000981

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00351

Gnomad ASJ AF: 0.0104

Gnomad EAS AF: 0.000981

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00482

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00491

Gnomad OTH AF: 0.00532

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00468 AC: 6760 AN: 1445818 Hom.: 12 AF XY: 0.00452 AC XY: 3246 AN XY: 718570

African (AFR) AF: 0.00119 AC: 39 AN: 32786

American (AMR) AF: 0.00302 AC: 129 AN: 42718

Ashkenazi Jewish (ASJ) AF: 0.0116 AC: 300 AN: 25866

East Asian (EAS) AF: 0.000130 AC: 5 AN: 38448

South Asian (SAS) AF: 0.000212 AC: 18 AN: 84908

European-Finnish (FIN) AF: 0.00559 AC: 289 AN: 51680

Middle Eastern (MID) AF: 0.00287 AC: 16 AN: 5568

European-Non Finnish (NFE) AF: 0.00517 AC: 5710 AN: 1104138

Other (OTH) AF: 0.00425 AC: 254 AN: 59706

GnomAD4 genome AF: 0.00351 AC: 528 AN: 150530 Hom.: 0 Cov.: 26 AF XY: 0.00314 AC XY: 231 AN XY: 73486

African (AFR) AF: 0.000978 AC: 40 AN: 40908

American (AMR) AF: 0.00350 AC: 53 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 36 AN: 3462

East Asian (EAS) AF: 0.000984 AC: 5 AN: 5082

South Asian (SAS) AF: 0.000212 AC: 1 AN: 4712

European-Finnish (FIN) AF: 0.00482 AC: 50 AN: 10366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00491 AC: 332 AN: 67584

Other (OTH) AF: 0.00526 AC: 11 AN: 2090

Alfa AF: 0.00329 Hom.: 12

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.9
Mutation Taster		=182/18	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs113070757; hg19: chr9-2039776;