NM_003070.5:c.693_707dupGCAGCAGCAGCAGCA

Variant names:

• chr9-2039776-A-ACAGCAGCAGCAGCAG
• rs113070757
• NM_003070.5:c.693_707dupGCAGCAGCAGCAGCA

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_707dupGCAGCAGCAGCAGCA​(p.Gln232_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 0.000126 in 150,532 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 INS_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. Q236Q) 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 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00
• 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: Orphanet, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen

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-A-ACAGCAGCAGCAGCAG is Benign according to our data. Variant chr9-2039776-A-ACAGCAGCAGCAGCAG is described in ClinVar as Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High AC in GnomAd4 at 19 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA2	NM_003070.5	MANE Select	c.693_707dupGCAGCAGCAGCAGCA	p.Gln232_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	NP_003061.3
	SMARCA2	NM_001289396.2		c.693_707dupGCAGCAGCAGCAGCA	p.Gln232_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	NP_001276325.1
	SMARCA2	NM_139045.4		c.693_707dupGCAGCAGCAGCAGCA	p.Gln232_Gln236dup	disruptive_inframe_insertion	Exon 4 of 33	NP_620614.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMARCA2	ENST00000349721.8	TSL:5 MANE Select	c.693_707dupGCAGCAGCAGCAGCA	p.Gln232_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	ENSP00000265773.5
	SMARCA2	ENST00000382203.5	TSL:1	c.693_707dupGCAGCAGCAGCAGCA	p.Gln232_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	ENSP00000371638.1
	SMARCA2	ENST00000450198.6	TSL:1	c.693_707dupGCAGCAGCAGCAGCA	p.Gln232_Gln236dup	disruptive_inframe_insertion	Exon 4 of 33	ENSP00000392081.2

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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000244 AC: 8 AN: 32784

American (AMR) AF: 0.0000468 AC: 2 AN: 42718

Ashkenazi Jewish (ASJ) AF: 0.0000387 AC: 1 AN: 25866

East Asian (EAS) AF: 0.0000260 AC: 1 AN: 38448

South Asian (SAS) AF: 0.000636 AC: 54 AN: 84906

European-Finnish (FIN) AF: 0.0000193 AC: 1 AN: 51680

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5568

European-Non Finnish (NFE) AF: 0.0000290 AC: 32 AN: 1104126

Other (OTH) AF: 0.0000335 AC: 2 AN: 59706

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

African (AFR) AF: 0.000220 AC: 9 AN: 40908

American (AMR) AF: 0.0000661 AC: 1 AN: 15128

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5082

South Asian (SAS) AF: 0.000637 AC: 3 AN: 4712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10366

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

European-Non Finnish (NFE) AF: 0.0000888 AC: 6 AN: 67586

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 12

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Benign:1

Sep 11, 2020

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 17, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.0
Mutation Taster		=86/14	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;