Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_000548.5(TSC2):c.1258-5G>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000373 in 1,607,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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 Likely_benign. Variant got -5 ACMG points.
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.82).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 16-2062492-G-T is Benign according to our data. Variant chr16-2062492-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 413674.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=2}.
Likely benign, criteria provided, single submitter
clinical testing
Invitae
Jan 18, 2024
- -
Likely benign, criteria provided, single submitter
clinical testing
Genome-Nilou Lab
Nov 07, 2021
- -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Jun 30, 2020
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter
curation
Sema4, Sema4
Jan 24, 2022
- -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Oct 15, 2015
- -
Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
All of Us Research Program, National Institutes of Health
Oct 02, 2023
This variant causes a G to T nucleotide substitution at the -5 position of intron 12 of the TSC2 gene. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 3/271128 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Benign:1
Likely benign, criteria provided, single submitter