rs948602

Variant names:

• chr18-47903874-T-A
• rs948602
• NM_005901.6:c.-53-7065A>T

Your query was ambiguous. Multiple possible variants found:

• chr18-47903874-T-A
• chr18-47903874-T-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.-53-7065A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.58 (8423 hom., cov: 7)
• Consequence: SMAD2 NM_005901.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.514
• Publications: 5 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 6

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

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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: 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 = 0.683 is higher than 0.05.

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.-53-7065A>T		intron	N/A	NP_005892.1	Q15796-1
	SMAD2	NM_001003652.4		c.-53-7065A>T		intron	N/A	NP_001003652.1	Q15796-1
	SMAD2	NM_001135937.3		c.-53-7065A>T		intron	N/A	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.-53-7065A>T		intron	N/A	ENSP00000262160.6	Q15796-1
	SMAD2	ENST00000402690.6	TSL:1	c.-53-7065A>T		intron	N/A	ENSP00000384449.1	Q15796-1
	SMAD2	ENST00000356825.8	TSL:1	c.-53-7065A>T		intron	N/A	ENSP00000349282.4	Q15796-2

Frequencies

GnomAD3 genomes AF: 0.582 AC: 34094 AN: 58620 Hom.: 8432 Cov.: 7

Gnomad AFR AF: 0.413

Gnomad AMI AF: 0.711

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.611

Gnomad EAS AF: 0.711

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.500

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.630

Gnomad OTH AF: 0.584

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

GnomAD4 genome AF: 0.581 AC: 34073 AN: 58596 Hom.: 8423 Cov.: 7 AF XY: 0.578 AC XY: 15410 AN XY: 26662

African (AFR) AF: 0.414 AC: 4889 AN: 11806

American (AMR) AF: 0.565 AC: 2156 AN: 3814

Ashkenazi Jewish (ASJ) AF: 0.611 AC: 1003 AN: 1642

East Asian (EAS) AF: 0.713 AC: 1476 AN: 2070

South Asian (SAS) AF: 0.701 AC: 1142 AN: 1628

European-Finnish (FIN) AF: 0.500 AC: 1130 AN: 2262

Middle Eastern (MID) AF: 0.556 AC: 40 AN: 72

European-Non Finnish (NFE) AF: 0.630 AC: 21388 AN: 33974

Other (OTH) AF: 0.582 AC: 431 AN: 740

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.472 AC: 1275 AN: 2700

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.18
DANN	Benign	0.62
PhyloP100		0.51
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs948602;

hg19: chr18-45430245;