rs45514391
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000548.5(TSC2):c.4579T>C(p.Phe1527Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,612,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F1527S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.4579T>C | p.Phe1527Leu | missense_variant | 36/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.4579T>C | p.Phe1527Leu | missense_variant | 36/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000986 AC: 15AN: 152196Hom.: 0 Cov.: 34
GnomAD3 exomes AF: 0.0000320 AC: 8AN: 249874Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135654
GnomAD4 exome AF: 0.00000753 AC: 11AN: 1460408Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 726506
GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152196Hom.: 0 Cov.: 34 AF XY: 0.0000941 AC XY: 7AN XY: 74364
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
TSC2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 17, 2022 | The TSC2 c.4579T>C variant is predicted to result in the amino acid substitution p.Phe1527Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.037% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2135240-T-C) and has conflicting interpretations of benign, likely benign, and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/49473/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 03, 2019 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 12, 2021 | 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. - |
Tuberous sclerosis syndrome Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at