rs2296212

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_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. 13/20 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

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 links:

LOC107987043 (HGNC:):

LOC107987043 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

PP2

Missense variant in the SMARCA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 88 curated benign missense variants. Gene score misZ: 5.054 (above the threshold of 3.09). Trascript score misZ: 4.663 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability-sparse hair-brachydactyly syndrome, Coffin-Siris syndrome 1.

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 id 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

GnomAD3 exomes

AF:

0.169

AC:

42451

AN:

251364

Hom.:

4359

AF XY:

0.167

AC XY:

22693

AN XY:

135866

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 SAS exome

AF:

0.257

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

Gnomad4 AFR exome

AF:

0.277

Gnomad4 AMR exome

AF:

0.236

Gnomad4 ASJ exome

AF:

0.0955

Gnomad4 EAS exome

AF:

0.191

Gnomad4 SAS exome

AF:

0.254

Gnomad4 FIN exome

AF:

0.133

Gnomad4 NFE exome

AF:

0.115

Gnomad4 OTH exome

AF:

0.148

GnomAD4 genome

AF:

0.172

AC:

26209

AN:

152162

Hom.:

2599

Cov.:

AF XY:

0.176

AC XY:

13075

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.271

Gnomad4 AMR

AF:

0.180

Gnomad4 ASJ

AF:

0.101

Gnomad4 EAS

AF:

0.211

Gnomad4 SAS

AF:

0.253

Gnomad4 FIN

AF:

0.136

Gnomad4 NFE

AF:

0.113

Gnomad4 OTH

AF:

0.163

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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;.;.;.;.;.;.;.;.;.;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over