rs1787199

Variant names:

• chr18-47878232-T-A
• rs1787199
• NM_005901.6:c.237-7668A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005901.6(SMAD2):​c.237-7668A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.402 in 152,012 control chromosomes in the GnomAD database, including 13,087 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.40 (13086 hom., cov: 32)
  • Exomes 𝑓: 0.75 (1 hom.)
• Consequence: SMAD2 NM_005901.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.310
• Publications: 8 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: Ambry Genetics, ClinGen
• Loeys-Dietz syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Loeys-Dietz syndrome 6

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

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet

ENSG00000269365 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.575 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD2	NM_005901.6	c.237-7668A>T		intron_variant	Intron 2 of 10	ENST00000262160.11	NP_005892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD2	ENST00000262160.11	c.237-7668A>T		intron_variant	Intron 2 of 10	1	NM_005901.6	ENSP00000262160.6

Frequencies

GnomAD3 genomes AF: 0.403 AC: 61147 AN: 151888 Hom.: 13092 Cov.: 32

Gnomad AFR AF: 0.269

Gnomad AMI AF: 0.640

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.458

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.379

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.466

Gnomad OTH AF: 0.420

GnomAD4 exome AF: 0.750 AC: 3 AN: 4 Hom.: 1 AF XY: 1.00 AC XY: 2 AN XY: 2

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.750 AC: 3 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.402 AC: 61143 AN: 152008 Hom.: 13086 Cov.: 32 AF XY: 0.399 AC XY: 29629 AN XY: 74284

African (AFR) AF: 0.269 AC: 11157 AN: 41486

American (AMR) AF: 0.361 AC: 5507 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.458 AC: 1588 AN: 3470

East Asian (EAS) AF: 0.592 AC: 3061 AN: 5168

South Asian (SAS) AF: 0.535 AC: 2575 AN: 4810

European-Finnish (FIN) AF: 0.379 AC: 3996 AN: 10540

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.466 AC: 31687 AN: 67960

Other (OTH) AF: 0.417 AC: 880 AN: 2112

Alfa AF: 0.431 Hom.: 1854

Bravo AF: 0.393

Asia WGS AF: 0.524 AC: 1824 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.20
DANN	Benign	0.35
PhyloP100		0.31
Mutation Taster		=100/0	polymorphism (auto)

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: rs1787199; hg19: chr18-45404603;