rs797044882

Positions:

• chr18-47848537-C-G
• chr18-47848537-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_005901.6(SMAD2):​c.935G>C​(p.Cys312Ser) 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. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD2 NM_005901.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.91

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a domain MH2 (size 193) in uniprot entity SMAD2_HUMAN there are 8 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 in gene, where missense usually causes diseases (based on misZ statistic), SMAD2. . Gene score misZ 3.6626 (greater than the threshold 3.09). Trascript score misZ 4.4705 (greater than threshold 3.09). GenCC has associacion of gene with Loeys-Dietz syndrome 6, congenital heart disease, familial thoracic aortic aneurysm and aortic dissection, Loeys-Dietz syndrome, congenital heart defects, multiple types, 8, with or without heterotaxy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.961
• PP5: Variant 18-47848537-C-G is Pathogenic according to our data. Variant chr18-47848537-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 208683.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr18-47848537-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SMAD2	NM_005901.6	c.935G>C	p.Cys312Ser	missense_variant	8/11	ENST00000262160.11	NP_005892.1
SMAD2	NM_001003652.4	c.935G>C	p.Cys312Ser	missense_variant	8/11		NP_001003652.1
SMAD2	NM_001135937.3	c.845G>C	p.Cys282Ser	missense_variant	7/10		NP_001129409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SMAD2	ENST00000262160.11	c.935G>C	p.Cys312Ser	missense_variant	8/11	1	NM_005901.6	ENSP00000262160

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 03, 2014

The c.935G>C (p.C312S) alteration is located in exon 8 (coding exon 7) of the SMAD2 gene. This alteration results from a G to C substitution at nucleotide position 935, causing the cysteine (C) at amino acid position 312 to be replaced by a serine (S). The alteration is not observed in healthy cohorts:_x000D_ Based on data from the NHLBI Exome Sequencing Project (ESP), the SMAD2 c.935G>C alteration was not observed among 6490 individuals tested. Allele frequency data for this nucleotide position are not currently available from the 1000 Genomes Project and the alteration is not currently listed in the Database of Single Nucleotide Polymorphisms (dbSNP). This nucleotide position is completely conserved on sequence alignment.This amino acid position is completely conserved on sequence alignment. The alteration is predicted deleterious by in silico models:_x000D_ The p.C312S alteration is predicted to be probably damaging by Polyphen and deleterious by SIFT in silico analyses. Based on the available evidence, this alteration is classified as pathogenic. -

Congenital heart defects, multiple types, 8, with or without heterotaxy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.98	D;D;.;.;D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;.;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.1	M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-9.8	D;D;D;.;.
REVEL	Pathogenic	0.82
Sift	Benign	0.080	T;T;T;.;.
Sift4G	Benign	0.11	T;T;T;T;T
Polyphen		1.0	D;D;D;D;D
Vest4		0.90
MutPred		0.90		Gain of disorder (P = 9e-04);Gain of disorder (P = 9e-04);.;.;.;
MVP		0.87
MPC		2.5
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.91
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: rs797044882; hg19: chr18-45374908;