18-47841890-C-G

Variant names:

• chr18-47841890-C-G
• rs2144276540
• NM_005901.6:c.1341G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_005901.6(SMAD2):​c.1341G>C​(p.Gln447His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q447Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMAD2 NM_005901.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.758
• Publications: 0 publications found

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]

SMAD2 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
• Loeys-Dietz syndrome 6

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• congenital heart defects, multiple types, 8, with or without heterotaxy

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• Loeys-Dietz syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SMAD2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.6626 (above the threshold of 3.09). Trascript score misZ: 4.4705 (above the threshold of 3.09). GenCC associations: The gene is linked to Loeys-Dietz syndrome 6, congenital heart disease, familial thoracic aortic aneurysm and aortic dissection, congenital heart defects, multiple types, 8, with or without heterotaxy, Loeys-Dietz syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005901.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD2	NM_005901.6	MANE Select	c.1341G>C	p.Gln447His	missense	Exon 11 of 11	NP_005892.1	Q15796-1
	SMAD2	NM_001003652.4		c.1341G>C	p.Gln447His	missense	Exon 11 of 11	NP_001003652.1	Q15796-1
	SMAD2	NM_001135937.3		c.1251G>C	p.Gln417His	missense	Exon 10 of 10	NP_001129409.1	Q15796-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD2	ENST00000262160.11	TSL:1 MANE Select	c.1341G>C	p.Gln447His	missense	Exon 11 of 11	ENSP00000262160.6	Q15796-1
	SMAD2	ENST00000402690.6	TSL:1	c.1341G>C	p.Gln447His	missense	Exon 11 of 11	ENSP00000384449.1	Q15796-1
	SMAD2	ENST00000356825.8	TSL:1	c.1251G>C	p.Gln417His	missense	Exon 10 of 10	ENSP00000349282.4	Q15796-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		0.76
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.79
MutPred		0.51		Loss of catalytic residue at Q447 (P = 0.02)
MVP		0.97
MPC		1.9
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.81
gMVP		0.97
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs2144276540; hg19: chr18-45368261;