rs281875198

chr9-2081902-G-C

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Moderate

The NM_003070.5(SMARCA2):c.2255G>C(p.Gly752Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G752R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 13 ACMG points.

• PM1: In a binding_site (size 7) in uniprot entity SMCA2_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_003070.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-2081901-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1032869.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP2: Missense variant where missense usually causes diseases, SMARCA2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant 9-2081902-G-C is Pathogenic according to our data. Variant chr9-2081902-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 30019.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-2081902-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA2	NM_003070.5	c.2255G>C	p.Gly752Ala	missense_variant	15/34	ENST00000349721.8
SMARCA2	NM_001289396.1	c.2255G>C	p.Gly752Ala	missense_variant	15/34
SMARCA2	NM_139045.4	c.2255G>C	p.Gly752Ala	missense_variant	15/33
SMARCA2	NM_001289397.2	c.2255G>C	p.Gly752Ala	missense_variant	15/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA2	ENST00000349721.8	c.2255G>C	p.Gly752Ala	missense_variant	15/34	5	NM_003070.5	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1 Other:1

not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 06, 2022	This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 752 of the SMARCA2 protein (p.Gly752Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Nicolaides-Baraitser syndrome and/or SMARCA2-related conditions (PMID: 22366787; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 30019). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMARCA2 protein function. For these reasons, this variant has been classified as Pathogenic. -

Nicolaides-Baraitser syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 26, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	4.7	H;.;H;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-5.7	D;.;D;D;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;D;D
Vest4		0.95
MutPred		0.96		Loss of catalytic residue at L753 (P = 0.1149);Loss of catalytic residue at L753 (P = 0.1149);Loss of catalytic residue at L753 (P = 0.1149);Loss of catalytic residue at L753 (P = 0.1149);Loss of catalytic residue at L753 (P = 0.1149);
MVP		1.0
MPC		1.5
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.98

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: rs281875198; hg19: chr9-2081902;