NM_003238.6:c.347-20856C>T

Variant names:

• chr1-218384313-C-T
• rs17047740
• NM_003238.6:c.347-20856C>T

Variant summary

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

The NM_003238.6(TGFB2):​c.347-20856C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0192 in 151,940 control chromosomes in the GnomAD database, including 58 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 0.019 (58 hom., cov: 33)
• Consequence: TGFB2 NM_003238.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.266
• Publications: 2 publications found

Genes affected

TGFB2 (HGNC:11768): (transforming growth factor beta 2) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate a latency-associated peptide (LAP) and a mature peptide, and is found in either a latent form composed of a mature peptide homodimer, a LAP homodimer, and a latent TGF-beta binding protein, or in an active form consisting solely of the mature peptide homodimer. The mature peptide may also form heterodimers with other TGF-beta family members. Disruption of the TGF-beta/SMAD pathway has been implicated in a variety of human cancers. A chromosomal translocation that includes this gene is associated with Peters' anomaly, a congenital defect of the anterior chamber of the eye. Mutations in this gene may be associated with Loeys-Dietz syndrome. This gene encodes multiple isoforms that may undergo similar proteolytic processing. [provided by RefSeq, Aug 2016]

TGFB2 Gene-Disease associations (from GenCC):

• Loeys-Dietz syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: Unknown, AD Classification: DEFINITIVE, 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=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0877 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003238.6. 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
	TGFB2	NM_003238.6	MANE Select	c.347-20856C>T		intron	N/A	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.431-20856C>T		intron	N/A	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.1713-20856C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.347-20856C>T		intron	N/A	ENSP00000355897.4	P61812-1
	TGFB2	ENST00000366929.4	TSL:1	c.431-20856C>T		intron	N/A	ENSP00000355896.4	P61812-2
	TGFB2	ENST00000488793.1	TSL:3	n.11-20856C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2921 AN: 151822 Hom.: 58 Cov.: 33

Gnomad AFR AF: 0.00534

Gnomad AMI AF: 0.0363

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.0948

Gnomad SAS AF: 0.00768

Gnomad FIN AF: 0.00879

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0232

Gnomad OTH AF: 0.0206

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

GnomAD4 genome AF: 0.0192 AC: 2919 AN: 151940 Hom.: 58 Cov.: 33 AF XY: 0.0185 AC XY: 1376 AN XY: 74274

African (AFR) AF: 0.00532 AC: 220 AN: 41324

American (AMR) AF: 0.0145 AC: 222 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 198 AN: 3468

East Asian (EAS) AF: 0.0946 AC: 490 AN: 5178

South Asian (SAS) AF: 0.00769 AC: 37 AN: 4814

European-Finnish (FIN) AF: 0.00879 AC: 93 AN: 10578

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0232 AC: 1578 AN: 68002

Other (OTH) AF: 0.0204 AC: 43 AN: 2106

Alfa AF: 0.0255 Hom.: 82

Bravo AF: 0.0212

Asia WGS AF: 0.0380 AC: 131 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.79
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism

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: rs17047740; hg19: chr1-218557655;