rs62534884

Positions:

• chr9-2039793-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_003070.5(SMARCA2):​c.683A>C​(p.Gln228Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0477 in 1,595,690 control chromosomes in the GnomAD database, including 1,950 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.039 (153 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1797 hom.)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.172

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SMARCA2. . Gene score misZ 5.054 (greater than the threshold 3.09). Trascript score misZ 4.663 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability-sparse hair-brachydactyly syndrome, Coffin-Siris syndrome 1.
• BP4: Computational evidence support a benign effect (MetaRNN=0.001706928).
• BP6: Variant 9-2039793-A-C is Benign according to our data. Variant chr9-2039793-A-C is described in ClinVar as [Benign]. Clinvar id is 126351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.683A>C	p.Gln228Pro	missense_variant	4/34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.1	c.683A>C	p.Gln228Pro	missense_variant	4/34		NP_001276325.1
SMARCA2	NM_139045.4	c.683A>C	p.Gln228Pro	missense_variant	4/33		NP_620614.2
SMARCA2	NM_001289397.2	c.683A>C	p.Gln228Pro	missense_variant	4/33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.683A>C	p.Gln228Pro	missense_variant	4/34	5	NM_003070.5	ENSP00000265773	P2

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5892 AN: 151810 Hom.: 153 Cov.: 32

Gnomad AFR AF: 0.00932

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0412

Gnomad ASJ AF: 0.0646

Gnomad EAS AF: 0.000966

Gnomad SAS AF: 0.0191

Gnomad FIN AF: 0.0388

Gnomad MID AF: 0.0350

Gnomad NFE AF: 0.0575

Gnomad OTH AF: 0.0451

GnomAD3 exomes AF: 0.0400 AC: 9200 AN: 230138 Hom.: 218 AF XY: 0.0406 AC XY: 5145 AN XY: 126674

Gnomad AFR exome AF: 0.00915

Gnomad AMR exome AF: 0.0340

Gnomad ASJ exome AF: 0.0650

Gnomad EAS exome AF: 0.000527

Gnomad SAS exome AF: 0.0182

Gnomad FIN exome AF: 0.0415

Gnomad NFE exome AF: 0.0557

Gnomad OTH exome AF: 0.0497

GnomAD4 exome AF: 0.0487 AC: 70266 AN: 1443764 Hom.: 1797 Cov.: 34 AF XY: 0.0483 AC XY: 34667 AN XY: 718060

Gnomad4 AFR exome AF: 0.00770

Gnomad4 AMR exome AF: 0.0349

Gnomad4 ASJ exome AF: 0.0613

Gnomad4 EAS exome AF: 0.000637

Gnomad4 SAS exome AF: 0.0194

Gnomad4 FIN exome AF: 0.0420

Gnomad4 NFE exome AF: 0.0546

Gnomad4 OTH exome AF: 0.0445

GnomAD4 genome AF: 0.0388 AC: 5895 AN: 151926 Hom.: 153 Cov.: 32 AF XY: 0.0371 AC XY: 2757 AN XY: 74254

Gnomad4 AFR AF: 0.00929

Gnomad4 AMR AF: 0.0411

Gnomad4 ASJ AF: 0.0646

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0194

Gnomad4 FIN AF: 0.0388

Gnomad4 NFE AF: 0.0575

Gnomad4 OTH AF: 0.0447

Alfa AF: 0.0465 Hom.: 77

Bravo AF: 0.0379

TwinsUK AF: 0.0359 AC: 133

ALSPAC AF: 0.0506 AC: 195

ExAC AF: 0.0352 AC: 3985

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Dec 31, 2014	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2016

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.7
DANN	Benign	0.79
DEOGEN2	Benign	0.022	.;.;T;T;T;T;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.71	.;T;.;.;.;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.60	N;.;.;N;.;.;N;.;N
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.7	N;N;.;N;.;.;N;.;N
REVEL	Benign	0.048
Sift	Benign	0.50	T;T;.;T;.;.;T;.;T
Sift4G	Benign	0.32	T;T;.;T;.;.;T;.;T
Polyphen		0.0	B;.;.;B;.;.;B;.;B
Vest4		0.15
MPC		0.054
ClinPred		0.0016	T
GERP RS		-0.30
Varity_R		0.11
gMVP		0.62

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

Other links and lift over

dbSNP: rs62534884; hg19: chr9-2039793; COSMIC: COSV61804952; COSMIC: COSV61804952;