NM_005901.6:c.-53-7065A>C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_005901.6(SMAD2):​c.-53-7065A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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 0.00061 (0 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

  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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD2	NM_005901.6	MANE Select	c.-53-7065A>C		intron	N/A	NP_005892.1
	SMAD2	NM_001003652.4		c.-53-7065A>C		intron	N/A	NP_001003652.1
	SMAD2	NM_001135937.3		c.-53-7065A>C		intron	N/A	NP_001129409.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SMAD2	ENST00000262160.11	TSL:1 MANE Select	c.-53-7065A>C		intron	N/A	ENSP00000262160.6
	SMAD2	ENST00000402690.6	TSL:1	c.-53-7065A>C		intron	N/A	ENSP00000384449.1
	SMAD2	ENST00000356825.8	TSL:1	c.-53-7065A>C		intron	N/A	ENSP00000349282.4

Frequencies

GnomAD3 genomes AF: 0.000608 AC: 36 AN: 59210 Hom.: 0 Cov.: 7

Gnomad AFR AF: 0.000837

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00129

Gnomad ASJ AF: 0.000600

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000599

Gnomad FIN AF: 0.000437

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000496

Gnomad OTH AF: 0.00135

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

GnomAD4 genome AF: 0.000608 AC: 36 AN: 59210 Hom.: 0 Cov.: 7 AF XY: 0.000816 AC XY: 22 AN XY: 26948

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000837 AC: 10 AN: 11944

American (AMR) AF: 0.00129 AC: 5 AN: 3880

Ashkenazi Jewish (ASJ) AF: 0.000600 AC: 1 AN: 1666

East Asian (EAS) AF: 0.00 AC: 0 AN: 2094

South Asian (SAS) AF: 0.000599 AC: 1 AN: 1670

European-Finnish (FIN) AF: 0.000437 AC: 1 AN: 2288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 76

European-Non Finnish (NFE) AF: 0.000496 AC: 17 AN: 34260

Other (OTH) AF: 0.00135 AC: 1 AN: 742

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.19
DANN	Benign	0.65
PhyloP100		0.51

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: rs948602; hg19: chr18-45430245;