rs1792689

Variant names:

• chr18-47842216-G-A
• rs1792689
• NM_005901.6:c.1281-266C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005901.6(SMAD2):​c.1281-266C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 152,012 control chromosomes in the GnomAD database, including 1,655 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.14 (1655 hom., cov: 32)
• Consequence: SMAD2 NM_005901.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0590
• Publications: 14 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 18-47842216-G-A is Benign according to our data. Variant chr18-47842216-G-A is described in ClinVar as Benign. ClinVar VariationId is 1181129.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SMAD2	NM_005901.6	c.1281-266C>T		intron_variant	Intron 10 of 10	ENST00000262160.11	NP_005892.1
SMAD2	NM_001003652.4	c.1281-266C>T		intron_variant	Intron 10 of 10		NP_001003652.1
SMAD2	NM_001135937.3	c.1191-266C>T		intron_variant	Intron 9 of 9		NP_001129409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SMAD2	ENST00000262160.11	c.1281-266C>T		intron_variant	Intron 10 of 10	1	NM_005901.6	ENSP00000262160.6
SMAD2	ENST00000402690.6	c.1281-266C>T		intron_variant	Intron 10 of 10	1		ENSP00000384449.1
SMAD2	ENST00000356825.8	c.1191-266C>T		intron_variant	Intron 9 of 9	1		ENSP00000349282.4
SMAD2	ENST00000586040.5	c.1191-266C>T		intron_variant	Intron 8 of 8	5		ENSP00000466193.1

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21544 AN: 151894 Hom.: 1650 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.295

Gnomad AMR AF: 0.101

Gnomad ASJ AF: 0.123

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.0791

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.124

Gnomad OTH AF: 0.129

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

GnomAD4 genome AF: 0.142 AC: 21550 AN: 152012 Hom.: 1655 Cov.: 32 AF XY: 0.139 AC XY: 10366 AN XY: 74318

African (AFR) AF: 0.191 AC: 7921 AN: 41430

American (AMR) AF: 0.100 AC: 1534 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.123 AC: 428 AN: 3466

East Asian (EAS) AF: 0.206 AC: 1065 AN: 5162

South Asian (SAS) AF: 0.164 AC: 789 AN: 4812

European-Finnish (FIN) AF: 0.0791 AC: 837 AN: 10582

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.124 AC: 8401 AN: 67974

Other (OTH) AF: 0.130 AC: 273 AN: 2108

Alfa AF: 0.129 Hom.: 4419

Bravo AF: 0.145

Asia WGS AF: 0.197 AC: 684 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.8
DANN	Benign	0.78
PhyloP100		0.059
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: rs1792689; hg19: chr18-45368587;