rs878854083
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_000548.5(TSC2):āc.244T>Cā(p.Trp82Arg) 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 Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
TSC2
NM_000548.5 missense
NM_000548.5 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 7.78
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.96
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.244T>C | p.Trp82Arg | missense_variant | 4/42 | ENST00000219476.9 | NP_000539.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.244T>C | p.Trp82Arg | missense_variant | 4/42 | 5 | NM_000548.5 | ENSP00000219476.3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1435108Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 711434
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1435108
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
711434
Gnomad4 AFR exome
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Gnomad4 ASJ exome
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Gnomad4 EAS exome
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Gnomad4 SAS exome
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Gnomad4 OTH exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
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 | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2017 | This sequence change replaces tryptophan with arginine at codon 82 of the TSC2 protein (p.Trp82Arg). The tryptophan residue is moderately conserved and there is a moderate physicochemical difference between tryptophan and arginine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 237991). This variant is not present in population databases (ExAC no frequency). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.;M;M;.;.;M;.;M;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;.;D;.;D;.;.;D;.;.;.;.;D
REVEL
Pathogenic
Sift
Uncertain
D;.;.;D;.;D;.;.;D;.;.;.;.;D
Sift4G
Uncertain
D;.;.;D;.;D;.;.;D;.;.;.;.;D
Polyphen
D;.;.;.;.;D;.;.;D;.;.;.;.;.
Vest4
MutPred
Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);.;Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);Gain of disorder (P = 0.0151);.;
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