NM_003238.6:c.511-12504G>T

Variant names:

• chr1-218421578-G-T
• rs1934852
• NM_003238.6:c.511-12504G>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.511-12504G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.376 in 151,842 control chromosomes in the GnomAD database, including 11,623 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 0.38 (11623 hom., cov: 31)
• Consequence: TGFB2 NM_003238.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.504
• Publications: 4 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):

• familial thoracic aortic aneurysm and aortic dissection

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.694 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFB2	NM_003238.6	c.511-12504G>T		intron_variant	Intron 2 of 6	ENST00000366930.9	NP_003229.1
TGFB2	NM_001135599.4	c.595-12504G>T		intron_variant	Intron 3 of 7		NP_001129071.1
TGFB2	NR_138148.2	n.1877-12504G>T		intron_variant	Intron 2 of 6
TGFB2	NR_138149.2	n.1961-12504G>T		intron_variant	Intron 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TGFB2	ENST00000366930.9	c.511-12504G>T		intron_variant	Intron 2 of 6	1	NM_003238.6	ENSP00000355897.4
TGFB2	ENST00000366929.4	c.595-12504G>T		intron_variant	Intron 3 of 7	1		ENSP00000355896.4
TGFB2	ENST00000488793.1	n.175-12504G>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56966 AN: 151720 Hom.: 11600 Cov.: 31

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.714

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.320

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.368

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

GnomAD4 genome AF: 0.376 AC: 57033 AN: 151842 Hom.: 11623 Cov.: 31 AF XY: 0.381 AC XY: 28250 AN XY: 74178

African (AFR) AF: 0.466 AC: 19259 AN: 41358

American (AMR) AF: 0.474 AC: 7236 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.325 AC: 1128 AN: 3468

East Asian (EAS) AF: 0.714 AC: 3684 AN: 5162

South Asian (SAS) AF: 0.368 AC: 1770 AN: 4804

European-Finnish (FIN) AF: 0.320 AC: 3360 AN: 10516

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.285 AC: 19388 AN: 67962

Other (OTH) AF: 0.371 AC: 783 AN: 2110

Alfa AF: 0.172 Hom.: 306

Bravo AF: 0.395

Asia WGS AF: 0.480 AC: 1672 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.36
DANN	Benign	0.50
PhyloP100		-0.50
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: rs1934852; hg19: chr1-218594920;