1-218414294-A-G

Variant names:

• chr1-218414294-A-G
• rs2000220
• NM_003238.6:c.510+8962A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_003238.6(TGFB2):​c.510+8962A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.572 in 151,826 control chromosomes in the GnomAD database, including 28,036 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 0.57 (28036 hom., cov: 31)
• Consequence: TGFB2 NM_003238.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.23
• Publications: 9 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.868 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.510+8962A>G		intron	N/A	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.594+8962A>G		intron	N/A	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.1876+8962A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.510+8962A>G		intron	N/A	ENSP00000355897.4	P61812-1
	TGFB2	ENST00000366929.4	TSL:1	c.594+8962A>G		intron	N/A	ENSP00000355896.4	P61812-2
	TGFB2	ENST00000488793.1	TSL:3	n.174+8962A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86686 AN: 151708 Hom.: 27973 Cov.: 31

Gnomad AFR AF: 0.875

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.601

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.738

Gnomad SAS AF: 0.587

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.398

Gnomad OTH AF: 0.551

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

GnomAD4 genome AF: 0.572 AC: 86808 AN: 151826 Hom.: 28036 Cov.: 31 AF XY: 0.574 AC XY: 42594 AN XY: 74160

African (AFR) AF: 0.876 AC: 36228 AN: 41378

American (AMR) AF: 0.601 AC: 9174 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1530 AN: 3466

East Asian (EAS) AF: 0.738 AC: 3808 AN: 5158

South Asian (SAS) AF: 0.586 AC: 2814 AN: 4802

European-Finnish (FIN) AF: 0.432 AC: 4535 AN: 10502

Middle Eastern (MID) AF: 0.480 AC: 141 AN: 294

European-Non Finnish (NFE) AF: 0.398 AC: 27056 AN: 67946

Other (OTH) AF: 0.553 AC: 1167 AN: 2112

Alfa AF: 0.466 Hom.: 50351

Bravo AF: 0.598

Asia WGS AF: 0.640 AC: 2226 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.61
PhyloP100		1.2
Mutation Taster		=99/1	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: rs2000220; hg19: chr1-218587636;