rs61736899

chr9-2191388-G-Achr9-2191388-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003070.5(SMARCA2):c.4717G>A(p.Asp1573Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00136 in 1,614,158 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 8.15

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]

LOC107987043 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, SMARCA2
• BP4: Computational evidence support a benign effect (MetaRNN=0.016689211).
• BP6: Variant 9-2191388-G-A is Benign according to our data. Variant chr9-2191388-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 366324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2191388-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00105 (160/152360) while in subpopulation NFE AF= 0.00168 (114/68040). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 73 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 160 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA2	NM_003070.5	c.4717G>A	p.Asp1573Asn	missense_variant	33/34	ENST00000349721.8
LOC107987043	XR_007061395.1	n.302-10366C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA2	ENST00000349721.8	c.4717G>A	p.Asp1573Asn	missense_variant	33/34	5	NM_003070.5	P2

Frequencies

GnomAD3 genomes AF: 0.00105 AC: 160 AN: 152242 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00168

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000931 AC: 234 AN: 251444 Hom.: 0 AF XY: 0.000905 AC XY: 123 AN XY: 135896

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00150

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00139 AC: 2033 AN: 1461798 Hom.: 2 Cov.: 31 AF XY: 0.00135 AC XY: 981 AN XY: 727206

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.000783

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.000394

Gnomad4 FIN exome AF: 0.000955

Gnomad4 NFE exome AF: 0.00164

Gnomad4 OTH exome AF: 0.00119

GnomAD4 genome AF: 0.00105 AC: 160 AN: 152360 Hom.: 0 Cov.: 33 AF XY: 0.000980 AC XY: 73 AN XY: 74512

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00168

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00129 Hom.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.000774 AC: 94

EpiCase AF: 0.00180

EpiControl AF: 0.00178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	SMARCA2: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Apr 28, 2017	BS1,BS2, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, was seen in a healthy adult where full penetrance of the disorder is expected at an early age, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 13, 2017	- -

Nicolaides-Baraitser syndrome Benign:2

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. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2022

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. -

SMARCA2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.23
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.017	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.048	D
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-2.1	N;.;N;N;N;.;.;.;N;N;N;N;.
REVEL	Benign	0.11
Sift	Uncertain	0.0050	D;.;D;D;D;.;.;.;D;D;D;D;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;T;T;T;T;T;T;T;D
Polyphen		0.46	P;.;B;P;B;.;.;B;B;.;B;.;.
Vest4		0.33
MVP		0.91
MPC		0.14
ClinPred		0.028	T
GERP RS		5.8
Varity_R		0.14
gMVP		0.10

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: rs61736899; hg19: chr9-2191388;