9-2039776-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP3BP6

The NM_003070.5(SMARCA2):c.690_707dupGCAGCAGCAGCAGCAGCA(p.Gln231_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 0.0000199 in 150,432 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q236Q) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000075 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SMARCA2
NM_003070.5 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

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: Likely_benign. The variant received -2 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003070.5

BP6

Variant 9-2039776-A-ACAGCAGCAGCAGCAGCAG is Benign according to our data. Variant chr9-2039776-A-ACAGCAGCAGCAGCAGCAG is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126352.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SMARCA2	NM_003070.5 link	c.690_707dupGCAGCAGCAGCAGCAGCA	p.Gln231_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2 link	c.690_707dupGCAGCAGCAGCAGCAGCA	p.Gln231_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34		NP_001276325.1
SMARCA2	NM_139045.4 link	c.690_707dupGCAGCAGCAGCAGCAGCA	p.Gln231_Gln236dup	disruptive_inframe_insertion	Exon 4 of 33		NP_620614.2
SMARCA2	NM_001289397.2 link	c.690_707dupGCAGCAGCAGCAGCAGCA	p.Gln231_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.690_707dupGCAGCAGCAGCAGCAGCA	p.Gln231_Gln236dup	disruptive_inframe_insertion	Exon 4 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes

AF:

0.0000199

AC:

AN:

150432

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000965

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000747

AC:

108

AN:

1445768

Hom.:

Cov.:

AF XY:

0.0000710

AC XY:

AN XY:

718546

show subpopulations

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

African (AFR)

AF:

0.0000305

AC:

AN:

32786

American (AMR)

AF:

0.0000936

AC:

AN:

42718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25866

East Asian (EAS)

AF:

0.000156

AC:

AN:

38448

South Asian (SAS)

AF:

0.0000707

AC:

AN:

84904

European-Finnish (FIN)

AF:

0.0000580

AC:

AN:

51680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.0000761

AC:

AN:

1104094

Other (OTH)

AF:

0.0000670

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000199

AC:

AN:

150432

Hom.:

Cov.:

AF XY:

0.0000409

AC XY:

AN XY:

73378

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40792

American (AMR)

AF:

0.00

AC:

AN:

15108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5096

South Asian (SAS)

AF:

0.00

AC:

AN:

4728

European-Finnish (FIN)

AF:

0.0000965

AC:

AN:

10366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67592

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Coffin Siris/Intellectual Disability

Uncertain:1

Feb 14, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nicolaides-Baraitser syndrome

Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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