Genetic Variant SMARCA2:p.Gln234_Gln236dup (chr9-2039776-A-ACAGCAGCAG) – ACMG Classification: Benign (-17 pts)

Variant summary

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

The NM_003070.5(SMARCA2):c.699_707dupGCAGCAGCA(p.Gln234_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 0.0104 in 150,526 control chromosomes in the GnomAD database, including 19 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 0.010 ( 19 hom., cov: 26)

Exomes 𝑓: 0.0057 ( 9 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-ACAGCAGCAG is Benign according to our data. Variant chr9-2039776-A-ACAGCAGCAG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 587963.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 = 0.0104 (1572/150526) while in subpopulation SAS AF = 0.0374 (176/4712). AF 95% confidence interval is 0.0328. There are 19 homozygotes in GnomAd4. There are 752 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 1572 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMARCA2	NM_003070.5	MANE Select	c.699_707dupGCAGCAGCA	p.Gln234_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	NP_003061.3
SMARCA2	NM_001289396.2		c.699_707dupGCAGCAGCA	p.Gln234_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	NP_001276325.1
SMARCA2	NM_139045.4		c.699_707dupGCAGCAGCA	p.Gln234_Gln236dup	disruptive_inframe_insertion	Exon 4 of 33	NP_620614.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SMARCA2	ENST00000349721.8	TSL:5 MANE Select	c.699_707dupGCAGCAGCA	p.Gln234_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	ENSP00000265773.5
SMARCA2	ENST00000382203.5	TSL:1	c.699_707dupGCAGCAGCA	p.Gln234_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	ENSP00000371638.1
SMARCA2	ENST00000450198.6	TSL:1	c.699_707dupGCAGCAGCA	p.Gln234_Gln236dup	disruptive_inframe_insertion	Exon 4 of 33	ENSP00000392081.2

Frequencies

GnomAD3 genomes

AF:

0.0104

AC:

1570

AN:

150426

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0258

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00463

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.000589

Gnomad SAS

AF:

0.0376

Gnomad FIN

AF:

0.000289

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.00348

Gnomad OTH

AF:

0.00484

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00568

AC:

8208

AN:

1445438

Hom.:

Cov.:

AF XY:

0.00632

AC XY:

4542

AN XY:

718384

show subpopulations

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

African (AFR)

AF:

0.0273

AC:

893

AN:

32750

American (AMR)

AF:

0.00487

AC:

208

AN:

42716

Ashkenazi Jewish (ASJ)

AF:

0.00406

AC:

105

AN:

25864

East Asian (EAS)

AF:

0.000520

AC:

AN:

38448

South Asian (SAS)

AF:

0.0297

AC:

2516

AN:

84842

European-Finnish (FIN)

AF:

0.000677

AC:

AN:

51680

Middle Eastern (MID)

AF:

0.00233

AC:

AN:

5568

European-Non Finnish (NFE)

AF:

0.00363

AC:

4009

AN:

1103886

Other (OTH)

AF:

0.00685

AC:

409

AN:

59684

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.384

Heterozygous variant carriers

399

797

1196

1594

1993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<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:

0.0104

AC:

1572

AN:

150526

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

752

AN XY:

73486

show subpopulations

African (AFR)

AF:

0.0259

AC:

1059

AN:

40902

American (AMR)

AF:

0.00463

AC:

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.00404

AC:

AN:

3462

East Asian (EAS)

AF:

0.000590

AC:

AN:

5082

South Asian (SAS)

AF:

0.0374

AC:

176

AN:

4712

European-Finnish (FIN)

AF:

0.000289

AC:

AN:

10366

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00348

AC:

235

AN:

67586

Other (OTH)

AF:

0.00478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

142

213

284

355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

110

<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:

0.00268

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:5

May 17, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SMARCA2: BS1, BS2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

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

Oct 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

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 14, 2017

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.

Nicolaides-Baraitser syndrome;C5443984:Blepharophimosis-impaired intellectual development syndrome

Benign:1

Nov 17, 2021

Fulgent Genetics, Fulgent Genetics

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

(source)

Splicing

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

Publications

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9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over