rs141631268
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_000548.5(TSC2):c.1678G>A(p.Val560Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,736 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. V560A) has been classified as Uncertain significance.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.1678G>A | p.Val560Met | missense_variant | 16/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.1678G>A | p.Val560Met | missense_variant | 16/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250734Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135586
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461572Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727056
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 20, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies report this variant is associated with normal TSC2 protein levels, a mild reduction in TSC1 protein levels that did not reach statistical significance, and a mild increase in TORC1 activity that did not reach statistical significance (Hoogeveen-Westerveld et al., 2011); This variant is associated with the following publications: (PMID: 24055113, 21309039, 25525159, 25637381) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The TSC2 p.V560M variant was not identified in the literature but was identified in dbSNP (ID: rs141631268) and ClinVar (classified as uncertain significance by Fulgent Genetics, Ambry Genetics and two other submitters; and as likely benign by Invitae). The variant was identified in control databases in 3 of 250734 chromosomes at a frequency of 0.00001196 (Genome Aggregation Database March 6, 2019, v2.1.1). The p.V560 residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Tuberous sclerosis 2 Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Tuberous sclerosis syndrome Uncertain:1Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
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 | Oct 31, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 04, 2022 | The p.V560M variant (also known as c.1678G>A), located in coding exon 15 of the TSC2 gene, results from a G to A substitution at nucleotide position 1678. The valine at codon 560 is replaced by methionine, an amino acid with highly similar properties. This variant has been seen in an exome cohort, but cardiovascular history was not provided (Amendola LM et al. Genome Res, 2015 Mar;25:305-15). This alteration was also reported as an incidental finding from one of 1000 participants' exomes and was classified as a Variant of Uncertain Significance (Dorschner MO et al. Am J Hum Genet, 2013 Oct;93:631-40). (Xiong HY et al. Science, 2015 Jan;347:1254806). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at