rs757221445
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PM1PP3_StrongBP6BS2
The NM_000548.5(TSC2):c.4998C>A(p.Phe1666Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,304 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).
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.4998C>A | p.Phe1666Leu | missense_variant | 39/42 | ENST00000219476.9 | NP_000539.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.4998C>A | p.Phe1666Leu | missense_variant | 39/42 | 5 | NM_000548.5 | ENSP00000219476 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249546Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135530
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460228Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 726392
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152076Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74266
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 12, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 02, 2022 | The p.F1666L variant (also known as c.4998C>A), located in coding exon 38 of the TSC2 gene, results from a C to A substitution at nucleotide position 4998. The phenylalanine at codon 1666 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Tuberous sclerosis 2 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 15, 2023 | This missense variant replaces phenylalanine with leucine at codon 1666 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 not been reported in individuals affected with TSC2-related disorders in the literature. This variant has been identified in 3/280940 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 05, 2020 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at