16-2083763-G-A
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000548.5(TSC2):c.3952G>A(p.Glu1318Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,286 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
TSC2
NM_000548.5 missense
NM_000548.5 missense
Scores
3
8
8
Clinical Significance
Conservation
PhyloP100: 6.89
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 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.3952G>A | p.Glu1318Lys | missense_variant | 33/42 | ENST00000219476.9 | NP_000539.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.3952G>A | p.Glu1318Lys | missense_variant | 33/42 | 5 | NM_000548.5 | ENSP00000219476 |
Frequencies
GnomAD3 genomes Cov.: 34
GnomAD3 genomes
Cov.:
34
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1458286Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 725156
GnomAD4 exome
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AC:
1
AN:
1458286
Hom.:
Cov.:
32
AF XY:
AC XY:
0
AN XY:
725156
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 34
GnomAD4 genome
Cov.:
34
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 | Mar 13, 2019 | 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: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TSC2-related disease. This sequence change replaces glutamic acid with lysine at codon 1318 of the TSC2 protein (p.Glu1318Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
Sift
Benign
T;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Benign
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen
D;.;.;.;P;P;.;.;P;P;.;.;.;.;.
Vest4
MutPred
Gain of ubiquitination at E1318 (P = 0.0016);.;.;.;.;.;.;Gain of ubiquitination at E1318 (P = 0.0016);.;.;.;.;.;.;.;
MVP
ClinPred
D
GERP RS
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