TSC2
TSC complex subunit 2, the group of Armadillo like helical domain containing|TSC complex|Protein phosphatase 1 regulatory subunits
Basic information
Region (hg38): 16:2047966-2089491
Previous symbols: [ "TSC4" ]
Links
Phenotypes
GenCC
Source:
- lung lymphangioleiomyomatosis (Definitive), mode of inheritance: AD
- tuberous sclerosis 2 (Definitive), mode of inheritance: AD
- lymphangioleiomyomatosis (Strong), mode of inheritance: AD
- tuberous sclerosis 2 (Strong), mode of inheritance: AD
- tuberous sclerosis 2 (Strong), mode of inheritance: AD
- tuberous sclerosis 2 (Strong), mode of inheritance: AD
- tuberous sclerosis 2 (Definitive), mode of inheritance: AD
- tuberous sclerosis complex (Supportive), mode of inheritance: AD
- tuberous sclerosis (Definitive), mode of inheritance: AD
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Tuberous sclerosis 2; Lymphangioleiomyomatosis | AD | Cardiovascular; Neurologic; Oncologic; Pulmonary; Renal | 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 | Cardiovascular; Dental; Dermatologic; Neurologic; Oncologic; Ophthalmologic; Pulmonary; Renal | 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; 23852707 |
ClinVar
This is a list of variants' phenotypes submitted to
- Tuberous sclerosis 2 (7635 variants)
- Hereditary cancer-predisposing syndrome (3737 variants)
- not provided (1779 variants)
- Tuberous sclerosis syndrome (1712 variants)
- not specified (586 variants)
- Isolated focal cortical dysplasia type II (186 variants)
- Lymphangiomyomatosis;Isolated focal cortical dysplasia type II;Tuberous sclerosis 2 (108 variants)
- TSC2-related condition (63 variants)
- Lymphangiomyomatosis;Tuberous sclerosis 2;Isolated focal cortical dysplasia type II (60 variants)
- Isolated focal cortical dysplasia type II;Tuberous sclerosis 2;Lymphangiomyomatosis (56 variants)
- Lymphangiomyomatosis (48 variants)
- Isolated focal cortical dysplasia type II;Lymphangiomyomatosis;Tuberous sclerosis 2 (45 variants)
- Tuberous sclerosis 2;Lymphangiomyomatosis;Isolated focal cortical dysplasia type II (36 variants)
- Ovarian cancer (18 variants)
- Lymphangiomyomatosis;Tuberous sclerosis syndrome (17 variants)
- Autism spectrum disorder (14 variants)
- Inborn genetic diseases (13 variants)
- Tuberous sclerosis 2;Isolated focal cortical dysplasia type II;Lymphangiomyomatosis (12 variants)
- - (9 variants)
- Seizure (3 variants)
- Tuberous sclerosis 1 (3 variants)
- Tuberous sclerosis syndrome;Lymphangiomyomatosis (2 variants)
- See cases (2 variants)
- Intellectual disability (2 variants)
- Rhabdomyoma (2 variants)
- Everolimus response (2 variants)
- Intellectual disability, severe;Infantile spasms (1 variants)
- Abnormal cerebral morphology (1 variants)
- Tuberous sclerosis syndrome;Autism spectrum disorder (1 variants)
- Recurrent fever (1 variants)
- Neurodevelopmental delay;Seizure (1 variants)
- Neurodevelopmental disorder (1 variants)
- Hirschsprung disease, susceptibility to, 1 (1 variants)
- Hamartoma;Dental enamel pits (1 variants)
- Abnormality of the nervous system (1 variants)
- Tuberous sclerosis 2;Tuberous sclerosis syndrome (1 variants)
- Neoplasm of brain (1 variants)
- Focal cortical dysplasia;Cortical tubers (1 variants)
- Astroblastoma, MN1-altered (1 variants)
- Cortical tubers (1 variants)
- Bone osteosarcoma (1 variants)
- Polycystic kidney disease, adult type (1 variants)
- Vascular dementia (1 variants)
- TSC2-Related Disorder (1 variants)
- 6 conditions (1 variants)
- Neoplasm;Cortical tubers (1 variants)
- Tuberous sclerosis and lymphangiomyomatosis (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the TSC2 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 35 | 1701 | 23 | 1761 | ||
| missense | 47 | 89 | 2921 | 174 | 80 | 3311 |
| nonsense | 223 | 17 | 250 | |||
| start loss | 5 | |||||
| frameshift | 403 | 32 | 19 | 456 | ||
| inframe indel | 10 | 15 | 100 | 126 | ||
| splice donor/acceptor (+/-2bp) | 129 | 57 | 28 | 218 | ||
| splice region ? | 27 | 12 | 263 | 319 | 10 | 631 |
| non coding ? | 86 | 1001 | 109 | 1204 | ||
| Total | 819 | 207 | 3209 | 2883 | 213 |
Highest pathogenic variant AF is 0.00000657
Variants in TSC2
This is a list of pathogenic ClinVar variants found in the TSC2 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 16-2048008-A-G | Tuberous sclerosis syndrome | Uncertain significance (Jan 13, 2018) | ||
| 16-2048010-G-C | Tuberous sclerosis syndrome | Uncertain significance (Jan 13, 2018) | ||
| 16-2048013-G-T | Tuberous sclerosis syndrome • Lymphangiomyomatosis;Isolated focal cortical dysplasia type II;Tuberous sclerosis 2 | Uncertain significance (May 18, 2022) | ||
| 16-2048023-T-A | Tuberous sclerosis syndrome | Likely benign (Jan 13, 2018) | ||
| 16-2048030-G-C | Tuberous sclerosis syndrome | Benign/Likely benign (Jun 01, 2023) | ||
| 16-2048044-GAGCGCGGTGGCGCGG-CGCGCTC | not specified | Likely benign (Dec 24, 2015) | ||
| 16-2048044-G-GAGCGCGGT | not specified | Likely benign (Mar 14, 2016) | ||
| 16-2048047-C-G | Benign (Jul 10, 2015) | |||
| 16-2048047-CGCGGTGGCGCGGCGCGGGGT-C | Tuberous sclerosis 2 | Uncertain significance (Jan 05, 2024) | ||
| 16-2048050-G-T | not specified | Likely benign (Jan 18, 2018) | ||
| 16-2048055-C-T | not specified | Likely benign (Feb 05, 2016) | ||
| 16-2048057-C-T | not specified | Likely benign (Apr 02, 2013) | ||
| 16-2048057-CGGCGCGGGGTAAGT-C | Tuberous sclerosis 2 • Tuberous sclerosis syndrome | Uncertain significance (Dec 15, 2023) | ||
| 16-2048059-G-A | not specified • TSC2-related disorder | Likely benign (Mar 09, 2021) | ||
| 16-2048060-CGCGGGGTAAGTG-C | Tuberous sclerosis syndrome | Uncertain significance (Apr 03, 2023) | ||
| 16-2048061-G-A | not specified • Tuberous sclerosis syndrome | Conflicting classifications of pathogenicity (Jan 13, 2018) | ||
| 16-2048061-GCGGGGTAAGTGGCGGTCCCCA-G | Tuberous sclerosis 2 | Uncertain significance (Aug 30, 2023) | ||
| 16-2048066-G-C | Tuberous sclerosis 2;Lymphangiomyomatosis;Isolated focal cortical dysplasia type II • Isolated focal cortical dysplasia type II • Tuberous sclerosis 2 | Uncertain significance (Sep 26, 2023) | ||
| 16-2048066-G-T | not specified • Tuberous sclerosis 2 • Isolated focal cortical dysplasia type II • Tuberous sclerosis syndrome | Uncertain significance (Dec 22, 2023) | ||
| 16-2048067-T-C | not specified • Hereditary cancer-predisposing syndrome • TSC2-related disorder | Conflicting classifications of pathogenicity (Jan 26, 2024) | ||
| 16-2048067-TAAGTGGCGGTCCCCACGGGGC-T | Hereditary cancer-predisposing syndrome | Benign/Likely benign (Oct 09, 2020) | ||
| 16-2048070-G-T | not specified | Uncertain significance (Dec 07, 2016) | ||
| 16-2048199-C-T | Likely benign (Jun 14, 2018) | |||
| 16-2048569-C-T | not specified | Likely benign (Nov 27, 2017) | ||
| 16-2048570-C-T | not specified | Likely benign (Mar 16, 2018) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| TSC2 | protein_coding | protein_coding | ENST00000219476 | 41 | 41251 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 1.00 | 6.39e-13 | 125084 | 7 | 520 | 125611 | 0.00210 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | -0.330 | 1099 | 1.07e+3 | 1.03 | 0.0000753 | 11587 |
| Missense in Polyphen | 323 | 396.39 | 0.81485 | 4422 | ||
| Synonymous | -8.39 | 727 | 491 | 1.48 | 0.0000388 | 3737 |
| Loss of Function | 8.37 | 2 | 85.4 | 0.0234 | 0.00000432 | 1004 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.00326 | 0.00305 |
| Ashkenazi Jewish | 0.00120 | 0.00119 |
| East Asian | 0.00342 | 0.00327 |
| Finnish | 0.000740 | 0.000739 |
| European (Non-Finnish) | 0.00245 | 0.00243 |
| Middle Eastern | 0.00342 | 0.00327 |
| South Asian | 0.00259 | 0.00255 |
| Other | 0.00180 | 0.00180 |
dbNSFP
Source:
- 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.;
- Pathway
- 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);AMPK signaling pathway - Homo sapiens (human);Thermogenesis - Homo sapiens (human);Thyroid hormone signaling pathway - Homo sapiens (human);Longevity regulating pathway - Homo sapiens (human);Phospholipase D signaling pathway - Homo sapiens (human);Cellular senescence - Homo sapiens (human);Insulin signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);Leucine Stimulation on Insulin Signaling;AMP-activated Protein Kinase (AMPK) Signaling;Target Of Rapamycin (TOR) Signaling;Integrated Breast Cancer Pathway;Follicle Stimulating Hormone (FSH) signaling pathway;Signaling Pathways in Glioblastoma;Brain-Derived Neurotrophic Factor (BDNF) signaling pathway;Nanoparticle triggered autophagic cell death;Polycystic Kidney Disease Pathway;Wnt Signaling Pathway;BDNF-TrkB Signaling;PI3K-AKT-mTOR signaling pathway and therapeutic opportunities;ATM Signaling Network in Development and Disease;Angiopoietin Like Protein 8 Regulatory Pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;Pathways in clear cell renal cell carcinoma;PI3K-AKT-mTOR - VitD3 Signalling;PI3K-Akt Signaling Pathway;Insulin Signaling;Monoamine Transport;Disease;Signal Transduction;Gene expression (Transcription);mtor signaling pathway;Vesicle-mediated transport;TBC/RABGAPs;Membrane Trafficking;Generic Transcription Pathway;RNA Polymerase II Transcription;Inhibition of TSC complex formation by PKB;Energy dependent regulation of mTOR by LKB1-AMPK;mTOR signalling;insulin Mam;TP53 Regulates Metabolic Genes;Macroautophagy;Cellular responses to external stimuli;Rab regulation of trafficking;PIP3 activates AKT signaling;Transcriptional Regulation by TP53;Direct p53 effectors;Constitutive Signaling by AKT1 E17K in Cancer;PI3K/AKT Signaling in Cancer;AKT phosphorylates targets in the cytosol;Intracellular signaling by second messengers;mTOR signaling pathway;Diseases of signal transduction;Validated targets of C-MYC transcriptional repression;p38 signaling mediated by MAPKAP kinases;LKB1 signaling events;insulin
(Consensus)
Recessive Scores
- pRec
- 0.390
Intolerance Scores
- loftool
- 0.000276
- rvis_EVS
- -2.54
- rvis_percentile_EVS
- 0.87
Haploinsufficiency Scores
- pHI
- 0.878
- hipred
- Y
- hipred_score
- 0.783
- ghis
- 0.602
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- N
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.856
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Tsc2
- Phenotype
- homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region phenotype; reproductive system phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); normal phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); renal/urinary system phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); embryo phenotype; neoplasm;
Zebrafish Information Network
- Gene name
- tsc2
- Affected structure
- hepatocyte
- Phenotype tag
- abnormal
- Phenotype quality
- ballooning
Gene ontology
- Biological process
- neural tube closure;negative regulation of protein kinase activity;protein import into nucleus;endocytosis;heart development;protein localization;negative regulation of cell population proliferation;negative regulation of phosphatidylinositol 3-kinase signaling;viral process;vesicle-mediated transport;positive regulation of macroautophagy;regulation of endocytosis;negative regulation of Wnt signaling pathway;negative regulation of TOR signaling;anoikis;protein kinase B signaling;positive regulation of GTPase activity;regulation of insulin receptor signaling pathway;negative regulation of insulin receptor signaling pathway;insulin-like growth factor receptor signaling pathway;positive chemotaxis;regulation of small GTPase mediated signal transduction;regulation of cell cycle;negative regulation of protein kinase B signaling;negative regulation of mitophagy
- Cellular component
- nucleus;cytoplasm;lysosome;Golgi apparatus;cytosol;postsynaptic density;membrane;TSC1-TSC2 complex;perinuclear region of cytoplasm
- Molecular function
- GTPase activator activity;protein binding;phosphatase binding;small GTPase binding;protein homodimerization activity;Hsp90 protein binding