9-2029072-C-G

Variant names:

• chr9-2029072-C-G
• NM_003070.5:c.50C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_003070.5(SMARCA2):​c.50C>G​(p.Pro17Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000707 in 1,415,106 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMARCA2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 93 curated pathogenic missense variants (we use a threshold of 10). The gene has 88 curated benign missense variants. Gene score misZ: 5.054 (above the threshold of 3.09). Trascript score misZ: 4.663 (above the threshold of 3.09). GenCC associations: The gene is linked to intellectual disability-sparse hair-brachydactyly syndrome, Coffin-Siris syndrome 1.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMARCA2	NM_003070.5	c.50C>G	p.Pro17Arg	missense_variant	Exon 2 of 34	ENST00000349721.8	NP_003061.3
SMARCA2	NM_001289396.2	c.50C>G	p.Pro17Arg	missense_variant	Exon 2 of 34		NP_001276325.1
SMARCA2	NM_139045.4	c.50C>G	p.Pro17Arg	missense_variant	Exon 2 of 33		NP_620614.2
SMARCA2	NM_001289397.2	c.50C>G	p.Pro17Arg	missense_variant	Exon 2 of 33		NP_001276326.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMARCA2	ENST00000349721.8	c.50C>G	p.Pro17Arg	missense_variant	Exon 2 of 34	5	NM_003070.5	ENSP00000265773.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1415106 Hom.: 0 Cov.: 32 AF XY: 0.00000143 AC XY: 1 AN XY: 699872

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: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 17 of the SMARCA2 protein (p.Pro17Arg). This variant is not present in population databases (gnomAD no frequency). 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	0.58
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	.;.;T;D;T;T;T;.;T;T;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	.;D;.;.;.;D;D;D;D;D;D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.67	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.8	L;.;.;L;.;.;.;L;.;.;L
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.1	D;D;.;D;.;.;D;D;D;.;D
REVEL	Uncertain	0.63
Sift	Pathogenic	0.0	D;D;.;D;.;.;D;D;D;.;D
Sift4G	Uncertain	0.016	D;D;.;D;.;.;D;D;D;.;D
Polyphen		1.0	D;.;.;D;.;.;.;D;.;.;D
Vest4		0.70
MutPred		0.27		Gain of methylation at P17 (P = 0.0082);Gain of methylation at P17 (P = 0.0082);Gain of methylation at P17 (P = 0.0082);Gain of methylation at P17 (P = 0.0082);Gain of methylation at P17 (P = 0.0082);Gain of methylation at P17 (P = 0.0082);Gain of methylation at P17 (P = 0.0082);Gain of methylation at P17 (P = 0.0082);Gain of methylation at P17 (P = 0.0082);Gain of methylation at P17 (P = 0.0082);Gain of methylation at P17 (P = 0.0082);
MVP		0.76
MPC		0.049
ClinPred		0.95	D
GERP RS		5.4
Varity_R		0.61
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-2029072;