chr1-218436360-A-G

Variant names:

• chr1-218436360-A-G
• rs6684205
• NM_003238.6:c.932+213A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000366930.9(TGFB2):​c.932+213A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 151,930 control chromosomes in the GnomAD database, including 11,619 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.38 (11619 hom., cov: 32)
• Consequence: TGFB2 ENST00000366930.9 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.606
• Publications: 50 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 1-218436360-A-G is Benign according to our data. Variant chr1-218436360-A-G is described in ClinVar as Benign. ClinVar VariationId is 1292461.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.699 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000366930.9. 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.932+213A>G		intron	N/A	NP_003229.1
	TGFB2	NM_001135599.4		c.1016+213A>G		intron	N/A	NP_001129071.1
	TGFB2	NR_138148.2		n.2183+213A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TGFB2	ENST00000366930.9	TSL:1 MANE Select	c.932+213A>G		intron	N/A	ENSP00000355897.4
	TGFB2	ENST00000366929.4	TSL:1	c.1016+213A>G		intron	N/A	ENSP00000355896.4
	TGFB2	ENST00000479322.1	TSL:3	n.416+213A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56971 AN: 151812 Hom.: 11598 Cov.: 32

Gnomad AFR AF: 0.465

Gnomad AMI AF: 0.356

Gnomad AMR AF: 0.473

Gnomad ASJ AF: 0.325

Gnomad EAS AF: 0.719

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.285

Gnomad OTH AF: 0.369

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

GnomAD4 genome AF: 0.375 AC: 57037 AN: 151930 Hom.: 11619 Cov.: 32 AF XY: 0.381 AC XY: 28261 AN XY: 74248

African (AFR) AF: 0.465 AC: 19259 AN: 41410

American (AMR) AF: 0.473 AC: 7229 AN: 15270

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

East Asian (EAS) AF: 0.718 AC: 3688 AN: 5136

South Asian (SAS) AF: 0.371 AC: 1786 AN: 4812

European-Finnish (FIN) AF: 0.319 AC: 3364 AN: 10554

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

European-Non Finnish (NFE) AF: 0.285 AC: 19370 AN: 67960

Other (OTH) AF: 0.372 AC: 786 AN: 2114

Alfa AF: 0.350 Hom.: 9244

Bravo AF: 0.394

Asia WGS AF: 0.493 AC: 1716 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	5.4
DANN	Benign	0.75
PhyloP100		0.61
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: rs6684205; hg19: chr1-218609702;