Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BP6
The NM_000548.5(TSC2):c.2465C>T(p.Ala822Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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 Uncertain_significance. Variant got 0 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.40230465).
BP6
Variant 16-2074309-C-T is Benign according to our data. Variant chr16-2074309-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406081.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}. Variant chr16-2074309-C-T is described in Lovd as [Likely_benign].
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.A822V variant (also known as c.2465C>T), located in coding exon 21 of the TSC2 gene, results from a C to T substitution at nucleotide position 2465. The alanine at codon 822 is replaced by valine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -
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