9-2029099-T-C

Position:

• chr9-2029099-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_003070.5(SMARCA2):​c.77T>C​(p.Ile26Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SMARCA2 NM_003070.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.17

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.3491689).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA2	NM_003070.5	c.77T>C	p.Ile26Thr	missense_variant	2/34	ENST00000349721.8
SMARCA2	NM_001289396.1	c.77T>C	p.Ile26Thr	missense_variant	2/34
SMARCA2	NM_139045.4	c.77T>C	p.Ile26Thr	missense_variant	2/33
SMARCA2	NM_001289397.2	c.77T>C	p.Ile26Thr	missense_variant	2/33

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA2	ENST00000349721.8	c.77T>C	p.Ile26Thr	missense_variant	2/34	5	NM_003070.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000462 AC: 1 AN: 216582 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 117018

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000613

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1439992 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 714408

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 16, 2023

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 26 of the SMARCA2 protein (p.Ile26Thr). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with SMARCA2-related conditions. 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 not expected to disrupt SMARCA2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.097	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	.;.;T;T;T;T;T;.;T;T;T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	.;D;.;.;.;D;D;D;D;D;D
M_CAP	Benign	0.048	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.038	D
MutationAssessor	Benign	1.7	L;.;.;L;.;.;.;L;.;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-0.56	N;N;.;N;.;.;D;N;D;.;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D;D;.;D;.;.;D;D;D;.;D
Sift4G	Benign	0.20	T;T;.;T;.;.;T;T;T;.;T
Polyphen		0.56	P;.;.;B;.;.;.;P;.;.;B
Vest4		0.49
MutPred		0.27		Gain of glycosylation at I26 (P = 4e-04);Gain of glycosylation at I26 (P = 4e-04);Gain of glycosylation at I26 (P = 4e-04);Gain of glycosylation at I26 (P = 4e-04);Gain of glycosylation at I26 (P = 4e-04);Gain of glycosylation at I26 (P = 4e-04);Gain of glycosylation at I26 (P = 4e-04);Gain of glycosylation at I26 (P = 4e-04);Gain of glycosylation at I26 (P = 4e-04);Gain of glycosylation at I26 (P = 4e-04);Gain of glycosylation at I26 (P = 4e-04);
MVP		0.65
MPC		0.056
ClinPred		0.41	T
GERP RS		5.8
Varity_R		0.27
gMVP		0.041

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: rs1184325506; hg19: chr9-2029099;