GeneBe

TGFB2

protein-coding

transforming growth factor beta 2, the group of Transforming growth factor beta family

Gene summary

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]

MANE transcript

NM_003238.6

Inheritance

AD

ClinVar variants

P:120U:345B:187

Top phenotype

Loeys-Dietz syndrome, type 4

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr1:218,345,336-218,444,619

External References & Databases

Ensembl (ENSG00000092969)NCBI Gene (7042)OMIM (190220)HGNC:11768GenCCUniProt (P61812)AlphaFoldClinVar (TGFB2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~99.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

familial thoracic aortic aneurysm and aortic dissectionDEFINITIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0019625

Submitter: ClinGen

familial thoracic aortic aneurysm and aortic dissectionSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019625

Submitter: Orphanet

Loeys-Dietz syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013897

Submitter: Labcorp Genetics (formerly Invitae)

Loeys-Dietz syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013897

Submitter: Genomics England PanelApp

Loeys-Dietz syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013897

Submitter: PanelApp Australia

Loeys-Dietz syndrome 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013897

Submitter: G2P

Loeys-Dietz syndrome 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013897

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Loeys-Dietz syndrome, type 4AD

Manifestation: Cardiovascular; Craniofacial; Dermatologic; Musculoskeletal

Intervention: Cardiovascular

Rationale: Individuals may manifest with cardiovascular anomalies, including thoracic aortic aneurysm as well as cardiac valvular anomalies, and awareness may allow early diagnosis and preventive measures and medical management in order to decrease morbidity and mortality

Comments: Though manifestations may occur primarily in adults, surveillance in the pediatric period may be indicated

Refs: 20301312; 22772371; 22772368Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TGFB2 variants in ClinVar

21 Conditions Cataloged
Loeys-Dietz syndrome 4Total: 495
Familial thoracic aortic aneurysm and aortic dissectionTotal: 290
not providedTotal: 173
not specifiedTotal: 51
TGFB2-related disorderTotal: 21
Ehlers-Danlos syndromeTotal: 14
Cardiovascular phenotypeTotal: 5
Familial aortopathyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003238.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
1
clinvar
7
clinvar
173
clinvar
1
clinvar
 182
missense
5
clinvar
14
clinvar
329
clinvar
12
clinvar
1
clinvar
 361
nonsense
22
clinvar
10
clinvar
3
clinvar
 35
start loss
0
frameshift
37
clinvar
15
clinvar
4
clinvar
 56
splice donor/acceptor (+/-2bp)
1
clinvar
15
clinvar
2
clinvar
 18
Total66543451852652

Highest pathogenic variant AF is 0.00001987769

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003238.6RefSeqNP_003229.17MANE Select
ENST00000366930.9EnsemblENSP00000355897.47MANE Select
NM_001135599.4RefSeqNP_001129071.18Standard
ENST00000366929.4EnsemblENSP00000355896.48Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
tgfb2Danio rerio

Structure: palate

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Chronic myeloid leukemia - Homo sapiens (human)
  • Gastric cancer - Homo sapiens (human)
  • TGF-beta signaling pathway - Homo sapiens (human)
  • Renal cell carcinoma - Homo sapiens (human)
  • AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human)

Biological Process

  • cell morphogenesis
  • skeletal system development
  • angiogenesis
  • eye development
  • response to hypoxia

Molecular Function

  • amyloid-beta binding
  • signaling receptor binding
  • type II transforming growth factor beta receptor binding
  • cytokine activity
  • transforming growth factor beta receptor binding

Cellular Component

  • extracellular region
  • extracellular space
  • axon
  • platelet alpha granule lumen
  • neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000366929
Coding exons
8
Length
98385
Individuals with no LoFs
124655
Homozygous LoFs
0
Heterozygous LoFs
1
Defined
124656
p
0.00000401
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense2.131532470.6190.00001252903
Missense (PolyPhen)3998.3720.396451127
Synonymous-0.1499896.11.020.00000501836
Loss of Function4.16020.10.009.15e-7259

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transforming growth factor beta-2 proprotein: Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-2 (TGF-beta-2) chains, which constitute the regulatory and active subunit of TGF-beta-2, respectively. {ECO:0000250|UniProtKB:P01137, ECO:0000250|UniProtKB:P04202}.; FUNCTION: Transforming growth factor beta-2: Multifunctional protein that regulates various processes such as angiogenesis and heart development (PubMed:22772371, PubMed:22772368). Activation into mature form follows different steps: following cleavage of the proprotein in the Golgi apparatus, Latency-associated peptide (LAP) and Transforming growth factor beta-2 (TGF-beta-2) chains remain non-covalently linked rendering TGF-beta-2 inactive during storage in extracellular matrix (By similarity). At the same time, LAP chain interacts with 'milieu molecules', such as LTBP1 and LRRC32/GARP, that control activation of TGF-beta-2 and maintain it in a latent state during storage in extracellular milieus (By similarity). Once activated following release of LAP, TGF-beta-2 acts by binding to TGF-beta receptors (TGFBR1 and TGFBR2), which transduce signal (By similarity). {ECO:0000250|UniProtKB:P01137, ECO:0000250|UniProtKB:P04202, ECO:0000269|PubMed:22772368, ECO:0000269|PubMed:22772371}.;
Disease
DISEASE: Note=A chromosomal aberration involving TGFB2 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with HDAC9. {ECO:0000269|PubMed:12706107}.; DISEASE: Loeys-Dietz syndrome 4 (LDS4) [MIM:614816]: An aortic aneurysm syndrome with widespread systemic involvement. LDS4 is characterized by arterial tortuosity, aortic dissection, intracranial aneurysm and subarachnoid hemorrhage, hypertelorism, bifid uvula, pectus deformity, bicuspid aortic valve, arachnodactyly, scoliosis, foot deformities, dural ectasia, joint hyperflexibility, and thin skin with easy bruising and striae. {ECO:0000269|PubMed:22772368, ECO:0000269|PubMed:22772371}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in TGFB2 may be a cause of non-syndromic aortic disease (NSAD). NSAD is a frequently asymptomatic but potentially lethal disease characterized by thoracic aortic aneurysms and dissections without additional syndromic features. {ECO:0000269|PubMed:25046559}.;

Recessive Scores

pRec
0.876

Intolerance Scores

RVIS EVS
-0.05
RVIS percentile EVS
50.01

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.994

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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