18-47841847-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_005901.6(SMAD2):c.1384C>T(p.Arg462Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R462H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SMAD2 NM_005901.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.96

Genes affected

SMAD2 (HGNC:6768): (SMAD family member 2) The protein encoded by this gene belongs to the SMAD, a family of proteins similar to the gene products of the Drosophila gene 'mothers against decapentaplegic' (Mad) and the C. elegans gene Sma. SMAD proteins are signal transducers and transcriptional modulators that mediate multiple signaling pathways. This protein mediates the signal of the transforming growth factor (TGF)-beta, and thus regulates multiple cellular processes, such as cell proliferation, apoptosis, and differentiation. This protein is recruited to the TGF-beta receptors through its interaction with the SMAD anchor for receptor activation (SARA) protein. In response to TGF-beta signal, this protein is phosphorylated by the TGF-beta receptors. The phosphorylation induces the dissociation of this protein with SARA and the association with the family member SMAD4. The association with SMAD4 is important for the translocation of this protein into the nucleus, where it binds to target promoters and forms a transcription repressor complex with other cofactors. This protein can also be phosphorylated by activin type 1 receptor kinase, and mediates the signal from the activin. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a domain MH2 (size 193) in uniprot entity SMAD2_HUMAN there are 18 pathogenic changes around while only 0 benign (100%) in NM_005901.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMAD2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMAD2	NM_005901.6	c.1384C>T	p.Arg462Cys	missense_variant	11/11	ENST00000262160.11
SMAD2	NM_001003652.4	c.1384C>T	p.Arg462Cys	missense_variant	11/11
SMAD2	NM_001135937.3	c.1294C>T	p.Arg432Cys	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMAD2	ENST00000262160.11	c.1384C>T	p.Arg462Cys	missense_variant	11/11	1	NM_005901.6
SMAD2	ENST00000402690.6	c.1384C>T	p.Arg462Cys	missense_variant	11/11	1
SMAD2	ENST00000356825.8	c.1294C>T	p.Arg432Cys	missense_variant	10/10	1		P1
SMAD2	ENST00000586040.5	c.1294C>T	p.Arg432Cys	missense_variant	9/9	5		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 05, 2023

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. 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 SMAD2 protein function. ClinVar contains an entry for this variant (Variation ID: 1521943). This variant has not been reported in the literature in individuals affected with SMAD2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 462 of the SMAD2 protein (p.Arg462Cys). -

Loeys-Dietz syndrome 6 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Jun 24, 2022

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with SMAD2-related connective tissue disorder (PMID: 29967133). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. Rare examples of non-penetrance in Loeys-Dietz syndrome (LDS) have been documented, including somatic mosaicism (GeneReviews). (I) 0115 - Variants in this gene are known to have variable expressivity. Intrafamilial variability has been reported in LDS (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional MH2 domain (PMID: 29967133). Mutagenesis studies have shown that Arg-462 is important for specific recognition and phosphorylation of the C-terminal serine residues of Smad2 by the type I TGFbeta receptor (PMID: 15210694). (SP) 0710 - Another missense variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. The p.(Arg462His) variant has been reported as a VUS in ClinVar. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D;D;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.51	D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.1	M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.1	N;N;N;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;D;D;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.53
MutPred		0.37		Gain of catalytic residue at S464 (P = 0.0122);Gain of catalytic residue at S464 (P = 0.0122);.;.;
MVP		0.97
MPC		1.7
ClinPred		0.85	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.94

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: chr18-45368218; COSMIC: COSV51004391; COSMIC: COSV51004391;