rs772687631
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP6BS2
The NM_000548.5(TSC2):c.4795G>A(p.Val1599Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000285 in 1,612,842 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V1599A) has been classified as Uncertain significance.
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 | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.4795G>A | p.Val1599Met | missense_variant | 37/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.4795G>A | p.Val1599Met | missense_variant | 37/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152184Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000401 AC: 10AN: 249584Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135492
GnomAD4 exome AF: 0.0000253 AC: 37AN: 1460658Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19AN XY: 726634
GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152184Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 22, 2016 | - - |
Tuberous sclerosis 2 Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | - - |
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 | Nov 20, 2023 | This missense variant replaces valine with methionine at codon 1599 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 tuberous sclerosis complex in the literature. This variant has been identified in 10/249584 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. - |
TSC2-related condition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 08, 2023 | The TSC2 c.4795G>A variant is predicted to result in the amino acid substitution p.Val1599Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0098% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2136326-G-A) and is reported in ClinVar as uncertain and likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/238061/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 28, 2018 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at