rs150022335

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_003242.6(TGFBR2):c.617C>T(p.Thr206Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000551 in 1,614,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000055 ( 0 hom. )

Consequence

TGFBR2
NM_003242.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1

Conservation

PhyloP100: 0.675

Variant links:

Genes affected

TGFBR2 (HGNC:11773): (transforming growth factor beta receptor 2) The protein encoded by this gene is a transmembrane protein that has a protein kinase domain, forms a heterodimeric complex with TGF-beta receptor type-1, and binds TGF-beta. This receptor/ligand complex phosphorylates proteins, which then enter the nucleus and regulate the transcription of genes related to cell proliferation, cell cycle arrest, wound healing, immunosuppression, and tumorigenesis. Mutations in this gene have been associated with Marfan Syndrome, Loeys-Deitz Aortic Aneurysm Syndrome, and the development of various types of tumors. Alternatively spliced transcript variants encoding different isoforms have been characterized. [provided by RefSeq, Aug 2017]

TGFBR2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06431836).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000525 (8/152320) while in subpopulation SAS AF= 0.000414 (2/4830). AF 95% confidence interval is 0.0000729. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TGFBR2	NM_003242.6 link	c.617C>T	p.Thr206Met	missense_variant	Exon 4 of 7	ENST00000295754.10	NP_003233.4	P37173-1A3QNQ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TGFBR2	ENST00000295754.10 link	c.617C>T	p.Thr206Met	missense_variant	Exon 4 of 7	1	NM_003242.6	ENSP00000295754.5	P37173-1
TGFBR2	ENST00000359013.4 link	c.692C>T	p.Thr231Met	missense_variant	Exon 5 of 8	1		ENSP00000351905.4	P37173-2
TGFBR2	ENST00000672866.1 link	n.2213C>T		non_coding_transcript_exon_variant	Exon 4 of 7

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251142

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000554

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000882

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000252

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000945

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:3

Mar 13, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T206M variant (also known as c.617C>T), located in coding exon 4 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 617. The threonine at codon 206 is replaced by methionine, an amino acid with similar properties. This alteration has been reported in aortic dissection, aortic aneurysm, and Loeys-Dietz syndrome cohorts (Sakai H et al. Hum Genet, 2012 Apr;131:591-9; Li Z et al. Sci China Life Sci, 2018 Dec;61:1545-1553; Yang H et al. Orphanet J Rare Dis, 2020 Jan;15:6). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Feb 20, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant replaces threonine with methionine at codon 206 in the TGFBR2 protein. This variant is also known as c.692C>T, p.Thr231Met based on a different transcript NM_001024847.2. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with aortic aneurysm and dissection (PMID: 22001912, 30341550) and in one individual suspected of having Loeys-Dietz syndrome (PMID: 31915033). This variant has also been identified in 12/282550 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 206 of the TGFBR2 protein (p.Thr206Met). This variant is present in population databases (rs150022335, gnomAD 0.03%). This missense change has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 22001912, 30341550, 31915033, 34498425; internal data). This variant is also known as c.692C>T (p.Thr231Met). ClinVar contains an entry for this variant (Variation ID: 44659). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt TGFBR2 function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:2

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TGFBR2: PM2:Supporting, BP4 -

Oct 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30341550, 34498425, 31915033, 22001912, 31786580) -

not specified

Uncertain:1Benign:1

Apr 25, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 20, 2010

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as Uncertain Significance - Favor Pathogenic. -

Loeys-Dietz syndrome 2

Uncertain:1

Jun 17, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the TGFBR2 protein. This variant is also known as c.692C>T, p.Thr231Met based on a different transcript NM_001024847.2. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with aortic aneurysm and dissection (PMID: 22001912, 30341550) and in one individual suspected of having Loeys-Dietz syndrome (PMID: 31915033). This variant has also been identified in 12/282550 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

T;.

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.19

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.032

MetaRNN

Benign

0.064

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

N;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.0

N;N

REVEL

Benign

0.098

Sift

Benign

0.055

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.50

P;.

Vest4

0.053

MVP

0.87

MPC

0.56

ClinPred

0.020

GERP RS

3.5

Varity_R

0.051

gMVP

0.42

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over