GeneBe

TSC2

protein-coding

TSC complex subunit 2, the group of Armadillo like helical domain containing|TSC complex|Protein phosphatase 1 regulatory subunits

Gene summary

This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

Previous symbols:
  • TSC4

MANE transcript

NM_000548.5

Inheritance

AD

ClinVar variants

P:1510U:4660B:3554

Top phenotype

Tuberous sclerosis 2; Lymphangioleiomyomatosis

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr16:2,047,967-2,089,491

External References & Databases

Ensembl (ENSG00000103197)NCBI Gene (7249)OMIM (191092)HGNC:12363GenCCUniProt (P49815)AlphaFoldClinVar (TSC2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~41.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

tuberous sclerosis 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013199

Submitter: Ambry Genetics

tuberous sclerosis 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013199

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

lymphangioleiomyomatosisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011705

Submitter: Genomics England PanelApp

tuberous sclerosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013199

Submitter: Genomics England PanelApp

tuberous sclerosis 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013199

Submitter: G2P

tuberous sclerosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013199

Submitter: Labcorp Genetics (formerly Invitae)

tuberous sclerosis complexSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019341

Submitter: Orphanet

Clinical Genomic Database (CGD)

Tuberous sclerosis 2; LymphangioleiomyomatosisAD

Manifestation: Cardiovascular; Dental; Dermatologic; Neurologic; Oncologic; Ophthalmologic; Pulmonary; Renal

Intervention: Cardiovascular; Neurologic; Oncologic; Pulmonary; Renal

Rationale: Surveillance for and early treatment of tumors, as well as other manifestations affecting multiple organ systems (eg, renal anomalies, neurologic manifestations, pulmonary manifestations, and cardiac manifestations including arrhythmias) may reduce morbidity and mortality; Treatment with mTOR inhibitors may be beneficial related to neoplastic sequelae as well as related seizures; Lymphangiomyomatosis can occur as an isolated disorder or in association with TSC - the only effective therapy in late stage disease is transplant

Refs: 14421523; 2823681; 3210031; 2706800; 1303246; 8162074; 8534286; 8824721; 8782048; 9302281; 9132502; 9463313; 9579160; 11829138; 14985384; 15955990; 17003820; 17005952; 17120248; 17304050; 18722871; 18032745; 19258298; 19332694; 19419980; 21266383; 21813552; 20301399; 22189265; 22490766; 23158522; 23733802; 23743818; 23757617; 23796861; 23845174; 23852707Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TSC2 variants in ClinVar

52 Conditions Cataloged
Tuberous sclerosis 2Total: 9664
Hereditary cancer-predisposing syndromeTotal: 5890
Tuberous sclerosis syndromeTotal: 3572
not providedTotal: 2335
Isolated focal cortical dysplasia type IITotal: 844
not specifiedTotal: 695
LymphangiomyomatosisTotal: 649
TSC2-related disorderTotal: 378

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000548.5. 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
6
clinvar
7
clinvar
51
clinvar
2251
clinvar
157
clinvar
 2472
missense
75
clinvar
171
clinvar
4045
clinvar
1021
clinvar
108
clinvar
 5420
nonsense
282
clinvar
19
clinvar
66
clinvar
2
clinvar
 369
start loss
4
clinvar
2
clinvar
 6
frameshift
597
clinvar
92
clinvar
382
clinvar
4
clinvar
 1075
splice donor/acceptor (+/-2bp)
171
clinvar
86
clinvar
114
clinvar
10
clinvar
1
clinvar
 382
Total1131379466032882669724

Highest pathogenic variant AF is 0.000008296118

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 129 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000548.5RefSeqNP_000539.241MANE Select
ENST00000219476.9EnsemblENSP00000219476.341MANE Select
NM_001077183.3RefSeqNP_001070651.139Standard
NM_001114382.3RefSeqNP_001107854.140Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
tsc2Danio rerio

Structure: hepatocyte

Quality: ballooning

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • mTOR signaling pathway - Homo sapiens (human)
  • Choline metabolism in cancer - Homo sapiens (human)
  • p53 signaling pathway - Homo sapiens (human)
  • Autophagy - animal - Homo sapiens (human)

Biological Process

  • neural tube closure
  • negative regulation of protein kinase activity
  • protein import into nucleus
  • endocytosis
  • heart development

Molecular Function

  • GTPase activator activity
  • protein binding
  • phosphatase binding
  • small GTPase binding
  • protein homodimerization activity

Cellular Component

  • nucleus
  • cytoplasm
  • lysosome
  • Golgi apparatus
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000219476
Coding exons
41
Length
41251
Individuals with no LoFs
125084
Homozygous LoFs
7
Heterozygous LoFs
520
Defined
125611
p
0.00210
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.33010991.07e+31.030.000075311587
Missense (PolyPhen)323396.390.814854422
Synonymous-8.397274911.480.00003883737
Loss of Function8.37285.40.02340.000004321004

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00190.0017notable
Latino/Admixed American0.00140.0014notable
Ashkenazi Jewish0.00120.0012notable
East Asian0.00340.0033notable
Finnish0.000740.00074rare
European (Non-Finnish)0.00250.0024notable
South Asian0.00260.0026notable
Other0.00180.0018notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: In complex with TSC1, this tumor suppressor inhibits the nutrient-mediated or growth factor-stimulated phosphorylation of S6K1 and EIF4EBP1 by negatively regulating mTORC1 signaling (PubMed:12271141, PubMed:28215400). Acts as a GTPase-activating protein (GAP) for the small GTPase RHEB, a direct activator of the protein kinase activity of mTORC1 (PubMed:15340059). May also play a role in microtubule-mediated protein transport (By similarity). Also stimulates the intrinsic GTPase activity of the Ras-related proteins RAP1A and RAB5 (By similarity). {ECO:0000250|UniProtKB:P49816, ECO:0000269|PubMed:12271141, ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:28215400}.;
Disease
DISEASE: Tuberous sclerosis 2 (TSC2) [MIM:613254]: An autosomal dominant multi-system disorder that affects especially the brain, kidneys, heart, and skin. It is characterized by hamartomas (benign overgrowths predominantly of a cell or tissue type that occurs normally in the organ) and hamartias (developmental abnormalities of tissue combination). Clinical manifestations include epilepsy, learning difficulties, behavioral problems, and skin lesions. Seizures can be intractable and premature death can occur from a variety of disease-associated causes. {ECO:0000269|PubMed:10069705, ECO:0000269|PubMed:10205261, ECO:0000269|PubMed:10533067, ECO:0000269|PubMed:10570911, ECO:0000269|PubMed:10607950, ECO:0000269|PubMed:10732801, ECO:0000269|PubMed:10735580, ECO:0000269|PubMed:12271141, ECO:0000269|PubMed:15024740, ECO:0000269|PubMed:15340059, ECO:0000269|PubMed:15595939, ECO:0000269|PubMed:15963462, ECO:0000269|PubMed:8824881, ECO:0000269|PubMed:9302281, ECO:0000269|PubMed:9463313, ECO:0000269|PubMed:9829910}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Lymphangioleiomyomatosis (LAM) [MIM:606690]: Progressive and often fatal lung disease characterized by a diffuse proliferation of abnormal smooth muscle cells in the lungs. It affects almost exclusively young women and can occur as an isolated disorder or in association with tuberous sclerosis complex. {ECO:0000269|PubMed:10823953, ECO:0000269|PubMed:11829138}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Focal cortical dysplasia 2 (FCORD2) [MIM:607341]: A form of focal cortical dysplasia, a malformation of cortical development that results in medically refractory epilepsy in the pediatric population and in adults. FCORD2 is a severe form, with onset usually in childhood, characterized by disrupted cortical lamination and specific cytological abnormalities. It is classified in 2 subtypes: type IIA characterized by dysmorphic neurons and lack of balloon cells; type IIB with dysmorphic neurons and balloon cells. {ECO:0000269|PubMed:28215400}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.390

Intolerance Scores

LoFtool
0.000276
RVIS EVS
-2.54
RVIS percentile EVS
0.87

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.856

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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