chr1-218347653-A-G

Variant names:

• chr1-218347653-A-G
• rs6658835
• NM_003238.6:c.346+606A>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.346+606A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 151,960 control chromosomes in the GnomAD database, including 13,348 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 0.39 (13348 hom., cov: 31)
• Consequence: TGFB2 NM_003238.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.195
• Publications: 20 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-AS1 (HGNC:50628): (TGFB2 antisense RNA 1 (head to head))

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 (AFR) allele frequency at 95% confidence interval = 0.637 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.346+606A>G		intron	N/A	NP_003229.1	P61812-1
	TGFB2	NM_001135599.4		c.346+606A>G		intron	N/A	NP_001129071.1	P61812-2
	TGFB2	NR_138148.2		n.1712+606A>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.346+606A>G		intron	N/A	ENSP00000355897.4	P61812-1
	TGFB2	ENST00000366929.4	TSL:1	c.346+606A>G		intron	N/A	ENSP00000355896.4	P61812-2
	TGFB2-AS1	ENST00000774588.1		n.214T>C		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58442 AN: 151842 Hom.: 13313 Cov.: 31

Gnomad AFR AF: 0.643

Gnomad AMI AF: 0.340

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.316

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.268

Gnomad OTH AF: 0.348

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

GnomAD4 genome AF: 0.385 AC: 58538 AN: 151960 Hom.: 13348 Cov.: 31 AF XY: 0.383 AC XY: 28466 AN XY: 74290

African (AFR) AF: 0.643 AC: 26654 AN: 41436

American (AMR) AF: 0.296 AC: 4523 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.316 AC: 1096 AN: 3468

East Asian (EAS) AF: 0.380 AC: 1959 AN: 5162

South Asian (SAS) AF: 0.340 AC: 1633 AN: 4808

European-Finnish (FIN) AF: 0.311 AC: 3283 AN: 10548

Middle Eastern (MID) AF: 0.357 AC: 105 AN: 294

European-Non Finnish (NFE) AF: 0.268 AC: 18233 AN: 67952

Other (OTH) AF: 0.352 AC: 743 AN: 2112

Alfa AF: 0.186 Hom.: 397

Bravo AF: 0.398

Asia WGS AF: 0.369 AC: 1283 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	4.4
DANN	Benign	0.26
PhyloP100		-0.20
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: rs6658835; hg19: chr1-218520995;