rs45517408
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000548.5(TSC2):c.5167T>C(p.Ser1723Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. S1723L) 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_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.5167T>C | p.Ser1723Pro | missense_variant | 41/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.5167T>C | p.Ser1723Pro | missense_variant | 41/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TSC2 protein function. This variant has been observed in individual(s) with tuberous sclerosis (PMID: 11112665, Invitae). ClinVar contains an entry for this variant (Variation ID: 49949). This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with proline at codon 1723 of the TSC2 protein (p.Ser1723Pro). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and proline. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
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