9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP3BP6_Very_StrongBS1BS2

The NM_003070.5(SMARCA2):c.702_707dupGCAGCA(p.Gln235_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 0.00268 in 1,596,150 control chromosomes in the GnomAD database, including 26 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 0.0099 ( 25 hom., cov: 26)

Exomes 𝑓: 0.0019 ( 1 hom. )

Consequence

SMARCA2
NM_003070.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

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-ACAGCAG is Benign according to our data. Variant chr9-2039776-A-ACAGCAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 436800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00987 (1486/150520) while in subpopulation AFR AF = 0.0304 (1244/40896). AF 95% confidence interval is 0.029. There are 25 homozygotes in GnomAd4. There are 689 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 1486 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMARCA2	NM_003070.5 link	c.702_707dupGCAGCA	p.Gln235_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2 link	c.702_707dupGCAGCA	p.Gln235_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34		NP_001276325.1
SMARCA2	NM_139045.4 link	c.702_707dupGCAGCA	p.Gln235_Gln236dup	disruptive_inframe_insertion	Exon 4 of 33		NP_620614.2
SMARCA2	NM_001289397.2 link	c.702_707dupGCAGCA	p.Gln235_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.702_707dupGCAGCA	p.Gln235_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes

AF:

0.00987

AC:

1484

AN:

150420

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0305

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00430

Gnomad ASJ

AF:

0.0234

Gnomad EAS

AF:

0.000196

Gnomad SAS

AF:

0.000846

Gnomad FIN

AF:

0.0000965

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000888

Gnomad OTH

AF:

0.0121

GnomAD4 exome

AF:

0.00194

AC:

2798

AN:

1445630

Hom.:

Cov.:

AF XY:

0.00186

AC XY:

1337

AN XY:

718444

show subpopulations

African (AFR)

AF:

0.0310

AC:

1017

AN:

32756

American (AMR)

AF:

0.00255

AC:

109

AN:

42718

Ashkenazi Jewish (ASJ)

AF:

0.0198

AC:

513

AN:

25864

East Asian (EAS)

AF:

0.00107

AC:

AN:

38448

South Asian (SAS)

AF:

0.00119

AC:

101

AN:

84782

European-Finnish (FIN)

AF:

0.000193

AC:

AN:

51680

Middle Eastern (MID)

AF:

0.00287

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.000671

AC:

741

AN:

1104118

Other (OTH)

AF:

0.00419

AC:

250

AN:

59698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.411

Heterozygous variant carriers

181

361

542

722

903

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.00987

AC:

1486

AN:

150520

Hom.:

Cov.:

AF XY:

0.00938

AC XY:

689

AN XY:

73480

show subpopulations

African (AFR)

AF:

0.0304

AC:

1244

AN:

40896

American (AMR)

AF:

0.00430

AC:

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

AN:

3462

East Asian (EAS)

AF:

0.000197

AC:

AN:

5082

South Asian (SAS)

AF:

0.000849

AC:

AN:

4712

European-Finnish (FIN)

AF:

0.0000965

AC:

AN:

10366

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000888

AC:

AN:

67586

Other (OTH)

AF:

0.0120

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

133

199

266

332

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00405

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Apr 09, 2018

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

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

May 12, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:5

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Nov 20, 2020

GeneDx

Significance:Likely 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

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SMARCA2: BP3, BS1, BS2

Inborn genetic diseases

Benign:1

Jan 08, 2019

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.

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