9-2116037-G-A

Variant names:

• chr9-2116037-G-A
• rs6601
• NM_003070.5:c.3672G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003070.5(SMARCA2):​c.3672G>A​(p.Glu1224Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 1,612,202 control chromosomes in the GnomAD database, including 22,628 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (7917 hom., cov: 32)
  • Exomes 𝑓: 0.12 (14711 hom.)
• Consequence: SMARCA2 NM_003070.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.191
• Publications: 15 publications found

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 9-2116037-G-A is Benign according to our data. Variant chr9-2116037-G-A is described in ClinVar as [Benign]. Clinvar id is 126346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.191 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.586 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.3672G>A	p.Glu1224Glu	synonymous_variant	Exon 25 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.3672G>A	p.Glu1224Glu	synonymous_variant	Exon 25 of 34		NP_001276325.1
SMARCA2	NM_139045.4	c.3672G>A	p.Glu1224Glu	synonymous_variant	Exon 25 of 33		NP_620614.2
SMARCA2	NM_001289397.2	c.3498G>A	p.Glu1166Glu	synonymous_variant	Exon 25 of 33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.3672G>A	p.Glu1224Glu	synonymous_variant	Exon 25 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes AF: 0.234 AC: 35534 AN: 151964 Hom.: 7872 Cov.: 32

Gnomad AFR AF: 0.592

Gnomad AMI AF: 0.0932

Gnomad AMR AF: 0.113

Gnomad ASJ AF: 0.0798

Gnomad EAS AF: 0.0194

Gnomad SAS AF: 0.0926

Gnomad FIN AF: 0.0873

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.179

GnomAD2 exomes AF: 0.123 AC: 30639 AN: 249844 AF XY: 0.115

Gnomad AFR exome AF: 0.606

Gnomad AMR exome AF: 0.0649

Gnomad ASJ exome AF: 0.0919

Gnomad EAS exome AF: 0.0156

Gnomad FIN exome AF: 0.0898

Gnomad NFE exome AF: 0.105

Gnomad OTH exome AF: 0.109

GnomAD4 exome AF: 0.115 AC: 168002 AN: 1460120 Hom.: 14711 Cov.: 30 AF XY: 0.113 AC XY: 81859 AN XY: 726386

African (AFR) AF: 0.617 AC: 20602 AN: 33414

American (AMR) AF: 0.0715 AC: 3195 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0883 AC: 2306 AN: 26124

East Asian (EAS) AF: 0.0300 AC: 1190 AN: 39682

South Asian (SAS) AF: 0.0973 AC: 8383 AN: 86172

European-Finnish (FIN) AF: 0.0916 AC: 4889 AN: 53356

Middle Eastern (MID) AF: 0.140 AC: 806 AN: 5764

European-Non Finnish (NFE) AF: 0.107 AC: 118607 AN: 1110570

Other (OTH) AF: 0.133 AC: 8024 AN: 60342

GnomAD4 genome AF: 0.234 AC: 35634 AN: 152082 Hom.: 7917 Cov.: 32 AF XY: 0.227 AC XY: 16874 AN XY: 74362

African (AFR) AF: 0.593 AC: 24548 AN: 41430

American (AMR) AF: 0.112 AC: 1717 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 277 AN: 3470

East Asian (EAS) AF: 0.0195 AC: 101 AN: 5186

South Asian (SAS) AF: 0.0931 AC: 448 AN: 4814

European-Finnish (FIN) AF: 0.0873 AC: 925 AN: 10598

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7113 AN: 67978

Other (OTH) AF: 0.177 AC: 373 AN: 2110

Alfa AF: 0.151 Hom.: 4177

Bravo AF: 0.253

Asia WGS AF: 0.0950 AC: 330 AN: 3478

EpiCase AF: 0.108

EpiControl AF: 0.106

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Jul 31, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 13, 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

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.74
DANN	Benign	0.41
PhyloP100		-0.19
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6601; hg19: chr9-2116037; COSMIC: COSV61807520;