9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBA1

The NM_003070.5(SMARCA2):c.705_707dupGCA(p.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 0.0321 in 150,494 control chromosomes in the GnomAD database, including 130 homozygotes. 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 0.032 ( 130 hom., cov: 26)

Exomes 𝑓: 0.017 ( 34 hom. )

Failed GnomAD Quality Control

Consequence

SMARCA2
NM_003070.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.00

Publications

9 publications found

Variant links:

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

SMARCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP3

Nonframeshift variant in repetitive region in NM_003070.5

BP6

Variant 9-2039776-A-ACAG is Benign according to our data. Variant chr9-2039776-A-ACAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0657 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMARCA2	NM_003070.5 link	c.705_707dupGCA	p.Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2 link	c.705_707dupGCA	p.Gln236dup	disruptive_inframe_insertion	Exon 4 of 34		NP_001276325.1
SMARCA2	NM_139045.4 link	c.705_707dupGCA	p.Gln236dup	disruptive_inframe_insertion	Exon 4 of 33		NP_620614.2
SMARCA2	NM_001289397.2 link	c.705_707dupGCA	p.Gln236dup	disruptive_inframe_insertion	Exon 4 of 33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8 link	c.705_707dupGCA	p.Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes

AF:

0.0321

AC:

4824

AN:

150394

Hom.:

131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0679

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0168

Gnomad ASJ

AF:

0.0208

Gnomad EAS

AF:

0.0179

Gnomad SAS

AF:

0.0199

Gnomad FIN

AF:

0.0457

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0148

Gnomad OTH

AF:

0.0315

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0168

AC:

24355

AN:

1445666

Hom.:

Cov.:

AF XY:

0.0170

AC XY:

12189

AN XY:

718498

show subpopulations

African (AFR)

AF:

0.0687

AC:

2248

AN:

32738

American (AMR)

AF:

0.0151

AC:

644

AN:

42710

Ashkenazi Jewish (ASJ)

AF:

0.0172

AC:

445

AN:

25858

East Asian (EAS)

AF:

0.0172

AC:

663

AN:

38448

South Asian (SAS)

AF:

0.0202

AC:

1715

AN:

84904

European-Finnish (FIN)

AF:

0.0422

AC:

2179

AN:

51666

Middle Eastern (MID)

AF:

0.0214

AC:

119

AN:

5568

European-Non Finnish (NFE)

AF:

0.0136

AC:

15026

AN:

1104074

Other (OTH)

AF:

0.0220

AC:

1316

AN:

59700

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

Heterozygous variant carriers

1778

3557

5335

7114

8892

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

628

1256

1884

2512

3140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0321

AC:

4837

AN:

150494

Hom.:

130

Cov.:

AF XY:

0.0327

AC XY:

2405

AN XY:

73466

show subpopulations

African (AFR)

AF:

0.0679

AC:

2774

AN:

40884

American (AMR)

AF:

0.0172

AC:

260

AN:

15126

Ashkenazi Jewish (ASJ)

AF:

0.0208

AC:

AN:

3462

East Asian (EAS)

AF:

0.0179

AC:

AN:

5082

South Asian (SAS)

AF:

0.0199

AC:

AN:

4712

European-Finnish (FIN)

AF:

0.0457

AC:

474

AN:

10362

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0148

AC:

1003

AN:

67582

Other (OTH)

AF:

0.0312

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

211

421

632

842

1053

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00920

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Dec 18, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:3

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 08, 2017

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Inborn genetic diseases

Benign:1

Apr 24, 2018

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0

Mutation Taster

=86/14

polymorphism

(source)

Splicing

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over