chr1-218424517-C-T

Variant names:

• chr1-218424517-C-T
• rs1342586
• NM_003238.6:c.511-9565C>T

Variant summary

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

The NM_001135599.4(TGFB2):​c.595-9565C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 152,200 control chromosomes in the GnomAD database, including 4,395 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 0.23 (4395 hom., cov: 32)
• Consequence: TGFB2 NM_001135599.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.487
• Publications: 13 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135599.4. 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
	TGFB2	NM_003238.6	MANE Select	c.511-9565C>T		intron	N/A	NP_003229.1
	TGFB2	NM_001135599.4		c.595-9565C>T		intron	N/A	NP_001129071.1
	TGFB2	NR_138148.2		n.1877-9565C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.511-9565C>T		intron	N/A	ENSP00000355897.4
	TGFB2	ENST00000366929.4	TSL:1	c.595-9565C>T		intron	N/A	ENSP00000355896.4
	TGFB2	ENST00000488793.1	TSL:3	n.175-9565C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34580 AN: 152082 Hom.: 4389 Cov.: 32

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.339

Gnomad AMR AF: 0.321

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.228

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

GnomAD4 genome AF: 0.227 AC: 34594 AN: 152200 Hom.: 4395 Cov.: 32 AF XY: 0.232 AC XY: 17277 AN XY: 74416

African (AFR) AF: 0.159 AC: 6592 AN: 41522

American (AMR) AF: 0.321 AC: 4910 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 840 AN: 3472

East Asian (EAS) AF: 0.551 AC: 2851 AN: 5172

South Asian (SAS) AF: 0.290 AC: 1400 AN: 4820

European-Finnish (FIN) AF: 0.246 AC: 2601 AN: 10584

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.214 AC: 14554 AN: 68014

Other (OTH) AF: 0.228 AC: 483 AN: 2114

Alfa AF: 0.225 Hom.: 16178

Bravo AF: 0.234

Asia WGS AF: 0.356 AC: 1237 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.49
DANN	Benign	0.65
PhyloP100		0.49
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: rs1342586; hg19: chr1-218597859;