TSC2

Chr 16AD

TSC complex subunit 2

Also known as: LAM, PPP1R160, TSC4

NCBI Gene: 7249 ENSG00000103197 UniProt: P49815

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]

Primary Disease Associations & Inheritance

?Focal cortical dysplasia, type II, somaticMIM #607341

Lymphangioleiomyomatosis, somaticMIM #606690

Tuberous sclerosis-2MIM #613254

{TSC2 angiomyolipomas, renal, modifier of}MIM #613254

Tuberous sclerosis-2MIM #613254

574

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— TSC2

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Gene-Disease Validity (ClinGen)

tuberous sclerosis · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

78 Pathogenic / Likely Pathogenic· 325 VUS of 574 total submissions

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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.07LOEUF

pLI 1.000

Z-score 8.37

OE 0.02 (0.01–0.07)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.33Z-score

OE missense 1.03 (0.98–1.08)

1099 obs / 1068.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.02 (0.01–0.07)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.03 (0.98–1.08)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.48

0≤1.21.6

LoF obs/exp: 2 / 85.4Missense obs/exp: 1099 / 1068.6Syn Z: -8.39

ClinVar Variant Classifications

574 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61

Likely Pathogenic17

VUS325

Likely Benign154

Benign15

Conflicting2

Pathogenic

Likely Pathogenic

325

VUS

154

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	45	1	15	0	61
Likely Pathogenic	7	6	4	0	17
VUS	12	268	39	6	325
Likely Benign	0	3	85	66	154
Benign	0	11	1	3	15
Conflicting	—				2
Total	64	289	144	75	574

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TSC2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TSC2-related tuberous sclerosis

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. DisordersEyeSkinCancer

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

TSC COMPLEX SUBUNIT 2; TSC2

MIM #191092 · *

?Focal cortical dysplasia, type II, somatic

MIM #607341