Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000548.5(TSC2):c.2580T>A(p.Phe860Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F860F) has been classified as Benign.
TSC2 (HGNC:12363): (TSC complex subunit 2) 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]
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP3
?
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
MetaRNN computational evidence supports a deleterious effect, 0.958
Gain of phosphorylation at Y865 (P = 0.2308);Gain of phosphorylation at Y865 (P = 0.2308);Gain of phosphorylation at Y865 (P = 0.2308);.;Gain of phosphorylation at Y865 (P = 0.2308);Gain of phosphorylation at Y865 (P = 0.2308);Gain of phosphorylation at Y865 (P = 0.2308);Gain of phosphorylation at Y865 (P = 0.2308);.;Gain of phosphorylation at Y865 (P = 0.2308);Gain of phosphorylation at Y865 (P = 0.2308);Gain of phosphorylation at Y865 (P = 0.2308);Gain of phosphorylation at Y865 (P = 0.2308);Gain of phosphorylation at Y865 (P = 0.2308);.;