9-2110275-G-C

Position:

• chr9-2110275-G-C

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_003070.5(SMARCA2):​c.3314G>C​(p.Arg1105Pro) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1105C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 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]

SMARCA2 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a domain Helicase C-terminal (size 162) in uniprot entity SMCA2_HUMAN there are 25 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 chr9-2110274-C-T is described in Lovd as [Pathogenic].
• 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 9-2110275-G-C is Pathogenic according to our data. Variant chr9-2110275-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-2110275-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.3314G>C	p.Arg1105Pro	missense_variant	24/34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.1	c.3314G>C	p.Arg1105Pro	missense_variant	24/34		NP_001276325.1
SMARCA2	NM_139045.4	c.3314G>C	p.Arg1105Pro	missense_variant	24/33		NP_620614.2
SMARCA2	NM_001289397.2	c.3140G>C	p.Arg1047Pro	missense_variant	24/33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.3314G>C	p.Arg1105Pro	missense_variant	24/34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 17, 2023	ClinVar contains an entry for this variant (Variation ID: 68770). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg1105 amino acid residue in SMARCA2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 22366787). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individuals with Nicolaides-Baraitser syndrome (PMID: 22366787; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1105 of the SMARCA2 protein (p.Arg1105Pro). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2023	Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22366787, 35811451, 24090879) -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Nicolaides-Baraitser syndrome Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Child and Adolescent Psychiatry Residency Program, Foundation for Education and Research in Health Sciences	-	PS4: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls PM1: Located in a mutational hot spot and/or critical and well-established functional domain PM2: Absent from controls (or at extremely low frequency if recessive) from ExAC, 1000Genomas, A3raM, TOPMED, and population databases. PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (p.R1105H, p.R1105C) (Sousa, Hennekam; Nicolaides-Baraitser Syndrome International Consortium, 2014). PM6: variant described as de novo, without confirmatory maternity and paternity analysis. PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product [CADD = 34.0]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Jun 20, 2022	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;.;D;.;D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;.;D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.5	H;.;H;H;H
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.6	D;.;D;D;D
REVEL	Pathogenic	0.92
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		0.99
MutPred		0.86		Gain of ubiquitination at K1110 (P = 0.044);.;Gain of ubiquitination at K1110 (P = 0.044);Gain of ubiquitination at K1110 (P = 0.044);Gain of ubiquitination at K1110 (P = 0.044);
MVP		0.99
MPC		2.7
ClinPred		1.0	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs281875197; hg19: chr9-2110275;