rs142257684
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000548.5(TSC2):c.1609C>A(p.Arg537Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R537C) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
TSC2
NM_000548.5 missense
NM_000548.5 missense
Scores
3
10
6
Clinical Significance
Conservation
PhyloP100: 6.58
Genes affected
TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.1609C>A | p.Arg537Ser | missense_variant | 16/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.1609C>A | p.Arg537Ser | missense_variant | 16/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Tuberous sclerosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 16, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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 not expected to disrupt TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 406103). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 537 of the TSC2 protein (p.Arg537Ser). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Uncertain
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
B;.;.;.;P;B;.;.;B;B;.;.;.;.;.
Vest4
MutPred
Gain of phosphorylation at R537 (P = 0.0359);Gain of phosphorylation at R537 (P = 0.0359);Gain of phosphorylation at R537 (P = 0.0359);.;Gain of phosphorylation at R537 (P = 0.0359);Gain of phosphorylation at R537 (P = 0.0359);Gain of phosphorylation at R537 (P = 0.0359);Gain of phosphorylation at R537 (P = 0.0359);.;Gain of phosphorylation at R537 (P = 0.0359);Gain of phosphorylation at R537 (P = 0.0359);Gain of phosphorylation at R537 (P = 0.0359);Gain of phosphorylation at R537 (P = 0.0359);Gain of phosphorylation at R537 (P = 0.0359);.;
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at