rs1020561347
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_000548.5(TSC2):c.3802C>T(p.Arg1268Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000329 in 1,612,268 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. R1268H) has been classified as Likely benign.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.3802C>T | p.Arg1268Cys | missense_variant | 31/42 | ENST00000219476.9 | NP_000539.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.3802C>T | p.Arg1268Cys | missense_variant | 31/42 | 5 | NM_000548.5 | ENSP00000219476.3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152232Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249694Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135596
GnomAD4 exome AF: 0.0000342 AC: 50AN: 1460036Hom.: 0 Cov.: 31 AF XY: 0.0000289 AC XY: 21AN XY: 726346
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152232Hom.: 0 Cov.: 34 AF XY: 0.0000269 AC XY: 2AN XY: 74378
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 23, 2022 | The p.R1268C variant (also known as c.3802C>T), located in coding exon 30 of the TSC2 gene, results from a C to T substitution at nucleotide position 3802. The arginine at codon 1268 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is well 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 31, 2021 | - - |
Tuberous sclerosis 2 Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 05, 2024 | - - |
Uncertain significance, 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 | Jan 11, 2024 | This missense variant replaces arginine with cysteine at codon 1268 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 hereditary cancer in the literature. This variant has been identified in 1/249694 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. - |
Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 08, 2021 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously reported as a pathogenic or benign germline variant to our knowledge; This variant is associated with the following publications: (PMID: 24425785) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at