Genetic Variant SMARCA2:p.Gln233_Gln236del (chr9-2039776-ACAGCAGCAGCAG-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_003070.5(SMARCA2):c.696_707delGCAGCAGCAGCA(p.Gln233_Gln236del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000192 in 1,596,340 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 DEL_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).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 26)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

SMARCA2
NM_003070.5 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 1.94

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: PanelApp Australia, Orphanet, G2P, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
blepharophimosis-impaired intellectual development syndrome
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia

SMARCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_003070.5

BP6

Variant 9-2039776-ACAGCAGCAGCAG-A is Benign according to our data. Variant chr9-2039776-ACAGCAGCAGCAG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 588716.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000299 (45/150532) while in subpopulation SAS AF = 0.00106 (5/4712). AF 95% confidence interval is 0.000418. There are 0 homozygotes in GnomAd4. There are 23 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

BS2

High AC in GnomAd4 at 45 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	UniProt
SMARCA2	NM_003070.5	MANE Select	c.696_707delGCAGCAGCAGCA	p.Gln233_Gln236del	disruptive_inframe_deletion	Exon 4 of 34	NP_003061.3
SMARCA2	NM_001289396.2		c.696_707delGCAGCAGCAGCA	p.Gln233_Gln236del	disruptive_inframe_deletion	Exon 4 of 34	NP_001276325.1	P51531-1
SMARCA2	NM_139045.4		c.696_707delGCAGCAGCAGCA	p.Gln233_Gln236del	disruptive_inframe_deletion	Exon 4 of 33	NP_620614.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SMARCA2	ENST00000349721.8	TSL:5 MANE Select	c.696_707delGCAGCAGCAGCA	p.Gln233_Gln236del	disruptive_inframe_deletion	Exon 4 of 34	ENSP00000265773.5	P51531-1
SMARCA2	ENST00000382203.5	TSL:1	c.696_707delGCAGCAGCAGCA	p.Gln233_Gln236del	disruptive_inframe_deletion	Exon 4 of 34	ENSP00000371638.1	P51531-1
SMARCA2	ENST00000450198.6	TSL:1	c.696_707delGCAGCAGCAGCA	p.Gln233_Gln236del	disruptive_inframe_deletion	Exon 4 of 33	ENSP00000392081.2	F6VDE0

Frequencies

GnomAD3 genomes

AF:

0.000299

AC:

AN:

150432

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000539

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000265

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000785

Gnomad SAS

AF:

0.00106

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000133

Gnomad OTH

AF:

0.000484

GnomAD4 exome

AF:

0.000181

AC:

261

AN:

1445808

Hom.:

AF XY:

0.000207

AC XY:

149

AN XY:

718564

show subpopulations

African (AFR)

AF:

0.000641

AC:

AN:

32786

American (AMR)

AF:

0.000258

AC:

AN:

42718

Ashkenazi Jewish (ASJ)

AF:

0.0000387

AC:

AN:

25866

East Asian (EAS)

AF:

0.00120

AC:

AN:

38448

South Asian (SAS)

AF:

0.000565

AC:

AN:

84904

European-Finnish (FIN)

AF:

0.0000193

AC:

AN:

51680

Middle Eastern (MID)

AF:

0.00162

AC:

AN:

5566

European-Non Finnish (NFE)

AF:

0.0000951

AC:

105

AN:

1104134

Other (OTH)

AF:

0.000318

AC:

AN:

59706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

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:

0.000299

AC:

AN:

150532

Hom.:

Cov.:

AF XY:

0.000313

AC XY:

AN XY:

73486

show subpopulations

African (AFR)

AF:

0.000538

AC:

AN:

40908

American (AMR)

AF:

0.000264

AC:

AN:

15128

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.000787

AC:

AN:

5082

South Asian (SAS)

AF:

0.00106

AC:

AN:

4712

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000133

AC:

AN:

67586

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

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.:

Bravo

AF:

0.000264

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.9

Mutation Taster

=178/22

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-ACAGCAGCAGCAGCAGCAG

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

Computational scores

Splicing

Publications

Other links and lift over