rs375075952
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1PP3BS2
The NM_000548.5(TSC2):c.5266G>A(p.Glu1756Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,638 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1756D) has been classified as Likely benign.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.5266G>A | p.Glu1756Lys | missense_variant | 42/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.5266G>A | p.Glu1756Lys | missense_variant | 42/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152142Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 250172Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135678
GnomAD4 exome AF: 0.00000685 AC: 10AN: 1460496Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4AN XY: 726558
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152142Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3AN XY: 74314
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2020 | This variant is associated with the following publications: (PMID: 29778030, 29740858) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 14, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 09, 2022 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 19, 2021 | - - |
Tuberous sclerosis 2 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 30, 2023 | This missense variant replaces glutamic acid with lysine at codon 1756 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two patients with a suspected diagnosis of tuberous sclerosis (PMID: 29778030, 29740858). This variant has been identified in 6/250172 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at