rs4940086

Variant names:

• chr18-47919936-T-C
• rs4940086
• NM_005901.6:c.-54+10425A>G

Variant summary

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

The NM_005901.6(SMAD2):​c.-54+10425A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.258 in 152,210 control chromosomes in the GnomAD database, including 6,304 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 0.26 (6304 hom., cov: 33)
  • Exomes 𝑓: 0.25 (0 hom.)
• Consequence: SMAD2 NM_005901.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.889
• Publications: 22 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=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD2	NM_005901.6	c.-54+10425A>G		intron_variant	Intron 1 of 10	ENST00000262160.11	NP_005892.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD2	ENST00000262160.11	c.-54+10425A>G		intron_variant	Intron 1 of 10	1	NM_005901.6	ENSP00000262160.6

Frequencies

GnomAD3 genomes AF: 0.259 AC: 39360 AN: 152078 Hom.: 6313 Cov.: 33

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.332

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.332

Gnomad EAS AF: 0.388

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.326

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.290

GnomAD4 exome AF: 0.250 AC: 4 AN: 16 Hom.: 0 AF XY: 0.500 AC XY: 3 AN XY: 6

African (AFR) AF: 0.00 AC: 0 AN: 6

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: 0.400 AC: 4 AN: 10

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.258 AC: 39333 AN: 152194 Hom.: 6304 Cov.: 33 AF XY: 0.259 AC XY: 19281 AN XY: 74404

African (AFR) AF: 0.0669 AC: 2781 AN: 41546

American (AMR) AF: 0.258 AC: 3938 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.332 AC: 1152 AN: 3468

East Asian (EAS) AF: 0.387 AC: 2008 AN: 5182

South Asian (SAS) AF: 0.377 AC: 1818 AN: 4824

European-Finnish (FIN) AF: 0.326 AC: 3452 AN: 10588

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23203 AN: 67986

Other (OTH) AF: 0.287 AC: 604 AN: 2108

Alfa AF: 0.312 Hom.: 9482

Bravo AF: 0.243

Asia WGS AF: 0.327 AC: 1139 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	6.8
DANN	Benign	0.82
PhyloP100		0.89
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: rs4940086; hg19: chr18-45446307;