rs1792658

Variant names:

• chr18-47856234-A-C
• rs1792658
• NM_005901.6:c.731-4907T>G

Your query was ambiguous. Multiple possible variants found:

• chr18-47856234-A-C
• chr18-47856234-A-G
• chr18-47856234-A-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.731-4907T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 151,882 control chromosomes in the GnomAD database, including 5,153 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 0.25 (5153 hom., cov: 31)
• Consequence: SMAD2 NM_005901.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.103
• Publications: 19 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.462 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD2	NM_005901.6	c.731-4907T>G		intron_variant	Intron 6 of 10	ENST00000262160.11	NP_005892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD2	ENST00000262160.11	c.731-4907T>G		intron_variant	Intron 6 of 10	1	NM_005901.6	ENSP00000262160.6

Frequencies

GnomAD3 genomes AF: 0.250 AC: 37993 AN: 151764 Hom.: 5133 Cov.: 31

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.362

Gnomad ASJ AF: 0.200

Gnomad EAS AF: 0.479

Gnomad SAS AF: 0.358

Gnomad FIN AF: 0.190

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.262

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.251 AC: 38050 AN: 151882 Hom.: 5153 Cov.: 31 AF XY: 0.256 AC XY: 18981 AN XY: 74250

African (AFR) AF: 0.258 AC: 10701 AN: 41414

American (AMR) AF: 0.363 AC: 5538 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 694 AN: 3466

East Asian (EAS) AF: 0.478 AC: 2452 AN: 5130

South Asian (SAS) AF: 0.359 AC: 1726 AN: 4806

European-Finnish (FIN) AF: 0.190 AC: 2004 AN: 10550

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 13983 AN: 67956

Other (OTH) AF: 0.269 AC: 566 AN: 2106

Alfa AF: 0.213 Hom.: 5932

Bravo AF: 0.265

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.7
DANN	Benign	0.67
PhyloP100		-0.10
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: rs1792658; hg19: chr18-45382605;