1-218424986-C-G

Variant names:

• chr1-218424986-C-G
• rs4846478
• NM_003238.6:c.511-9096C>G

Variant summary

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

The NM_003238.6(TGFB2):​c.511-9096C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.331 in 152,054 control chromosomes in the GnomAD database, including 9,053 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 0.33 (9053 hom., cov: 32)
• Consequence: TGFB2 NM_003238.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0170
• Publications: 7 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, Unknown Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Loeys-Dietz syndrome 4

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.682 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.511-9096C>G		intron	N/A	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.595-9096C>G		intron	N/A	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.1877-9096C>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.511-9096C>G		intron	N/A	ENSP00000355897.4	P61812-1
	TGFB2	ENST00000366929.4	TSL:1	c.595-9096C>G		intron	N/A	ENSP00000355896.4	P61812-2
	TGFB2	ENST00000488793.1	TSL:3	n.175-9096C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50220 AN: 151936 Hom.: 9041 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.445

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.269

Gnomad OTH AF: 0.333

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

GnomAD4 genome AF: 0.331 AC: 50269 AN: 152054 Hom.: 9053 Cov.: 32 AF XY: 0.337 AC XY: 25018 AN XY: 74310

African (AFR) AF: 0.350 AC: 14520 AN: 41478

American (AMR) AF: 0.445 AC: 6800 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1067 AN: 3470

East Asian (EAS) AF: 0.701 AC: 3615 AN: 5156

South Asian (SAS) AF: 0.345 AC: 1668 AN: 4830

European-Finnish (FIN) AF: 0.304 AC: 3213 AN: 10564

Middle Eastern (MID) AF: 0.286 AC: 84 AN: 294

European-Non Finnish (NFE) AF: 0.269 AC: 18269 AN: 67978

Other (OTH) AF: 0.336 AC: 708 AN: 2106

Alfa AF: 0.301 Hom.: 894

Bravo AF: 0.346

Asia WGS AF: 0.457 AC: 1589 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.7
DANN	Benign	0.77
PhyloP100		0.017
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4846478;

hg19: chr1-218598328;