chr9-2191309-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003070.5(SMARCA2):c.4638C>G(p.Asp1546Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 1,613,644 control chromosomes in the GnomAD database, including 17,786 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2599 hom., cov: 33)

Exomes 𝑓: 0.13 ( 15187 hom. )

Consequence

SMARCA2
NM_003070.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.114

Publications

50 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:

ENSG00000306181 (HGNC:):

ENSG00000306181 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0035037398).

BP6

Variant 9-2191309-C-G is Benign according to our data. Variant chr9-2191309-C-G is described in ClinVar as Benign. ClinVar VariationId is 126349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5 link	c.4638C>G	p.Asp1546Glu	missense_variant	Exon 33 of 34	ENST00000349721.8	NP_003061.3	P51531-1Q8N9Q1Q56A76

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8 link	c.4638C>G	p.Asp1546Glu	missense_variant	Exon 33 of 34	5	NM_003070.5	ENSP00000265773.5		P51531-1

Frequencies

GnomAD3 genomes

AF:

0.172

AC:

26197

AN:

152044

Hom.:

2595

Cov.:

show subpopulations

Gnomad AFR

AF:

0.272

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.180

Gnomad ASJ

AF:

0.101

Gnomad EAS

AF:

0.212

Gnomad SAS

AF:

0.252

Gnomad FIN

AF:

0.136

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.113

Gnomad OTH

AF:

0.164

GnomAD2 exomes

AF:

0.169

AC:

42451

AN:

251364

AF XY:

0.167

show subpopulations

Gnomad AFR exome

AF:

0.283

Gnomad AMR exome

AF:

0.247

Gnomad ASJ exome

AF:

0.0954

Gnomad EAS exome

AF:

0.218

Gnomad FIN exome

AF:

0.133

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.155

GnomAD4 exome

AF:

0.134

AC:

196379

AN:

1461482

Hom.:

15187

Cov.:

AF XY:

0.137

AC XY:

99456

AN XY:

727048

show subpopulations

African (AFR)

AF:

0.277

AC:

9275

AN:

33464

American (AMR)

AF:

0.236

AC:

10547

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0955

AC:

2494

AN:

26126

East Asian (EAS)

AF:

0.191

AC:

7583

AN:

39694

South Asian (SAS)

AF:

0.254

AC:

21939

AN:

86226

European-Finnish (FIN)

AF:

0.133

AC:

7100

AN:

53410

Middle Eastern (MID)

AF:

0.176

AC:

1018

AN:

5768

European-Non Finnish (NFE)

AF:

0.115

AC:

127500

AN:

1111710

Other (OTH)

AF:

0.148

AC:

8923

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

8168

16336

24504

32672

40840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4916

9832

14748

19664

24580

<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:

0.172

AC:

26209

AN:

152162

Hom.:

2599

Cov.:

AF XY:

0.176

AC XY:

13075

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.271

AC:

11254

AN:

41504

American (AMR)

AF:

0.180

AC:

2750

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.101

AC:

350

AN:

3472

East Asian (EAS)

AF:

0.211

AC:

1095

AN:

5180

South Asian (SAS)

AF:

0.253

AC:

1220

AN:

4816

European-Finnish (FIN)

AF:

0.136

AC:

1436

AN:

10580

Middle Eastern (MID)

AF:

0.153

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.113

AC:

7688

AN:

68006

Other (OTH)

AF:

0.163

AC:

344

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1096

2192

3289

4385

5481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

286

572

858

1144

1430

<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:

0.129

Hom.:

460

Bravo

AF:

0.181

TwinsUK

AF:

0.123

AC:

457

ALSPAC

AF:

0.119

AC:

459

ESP6500AA

AF:

0.269

AC:

1187

ESP6500EA

AF:

0.112

AC:

962

ExAC

AF:

0.168

AC:

20440

Asia WGS

AF:

0.242

AC:

839

AN:

3478

EpiCase

AF:

0.116

EpiControl

AF:

0.117

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 03, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19363039) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases

Benign:1

Mar 16, 2016

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

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

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

Benign:1

Dec 06, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.55

DEOGEN2

Benign

0.11

.;.;T;.;T;.;.;T;.;.;T;.;.;T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.21

.;T;.;T;T;T;.;.;T;T;T;T;T;T;T

MetaRNN

Benign

0.0029

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.6

.;.;N;.;N;.;.;.;.;.;.;.;.;.;.

PhyloP100

0.11

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.54

N;.;N;N;N;.;.;.;N;N;N;N;.;.;.

REVEL

Benign

0.095

Sift

Benign

1.0

T;.;T;T;T;.;.;.;T;T;T;T;.;.;.

Sift4G

Benign

0.61

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0

B;.;B;B;B;.;.;B;B;.;B;.;.;.;.

Vest4

0.099

MutPred

0.039

.;.;Gain of methylation at K1547 (P = 0.1355);.;Gain of methylation at K1547 (P = 0.1355);.;.;.;.;.;.;.;.;.;.;

MPC

0.13

ClinPred

0.0091

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.041

gMVP

0.034

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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