rs201525586
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_000548.5(TSC2):āc.1131C>Gā(p.Ser377Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,182 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 33)
Consequence
TSC2
NM_000548.5 missense
NM_000548.5 missense
Scores
2
10
7
Clinical Significance
Conservation
PhyloP100: 0.767
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 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 16-2061882-C-G is Benign according to our data. Variant chr16-2061882-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1002448.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.1131C>G | p.Ser377Arg | missense_variant | 12/42 | ENST00000219476.9 | NP_000539.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.1131C>G | p.Ser377Arg | missense_variant | 12/42 | 5 | NM_000548.5 | ENSP00000219476.3 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 33
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GnomAD4 exome Cov.: 32
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152182Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74338
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Tuberous sclerosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 30, 2022 | This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 377 of the TSC2 protein (p.Ser377Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1002448). 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. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 2022 | The p.S377R variant (also known as c.1131C>G), located in coding exon 11 of the TSC2 gene, results from a C to G substitution at nucleotide position 1131. The serine at codon 377 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18466115) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
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
Benign
T
MutationAssessor
Benign
L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
Sift
Benign
D;.;.;T;.;T;.;.;T;D;.;.;.;.;T
Sift4G
Uncertain
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
D;.;.;.;D;D;.;.;D;P;.;.;.;.;.
Vest4
MutPred
Gain of catalytic residue at S377 (P = 0.0464);Gain of catalytic residue at S377 (P = 0.0464);Gain of catalytic residue at S377 (P = 0.0464);.;Gain of catalytic residue at S377 (P = 0.0464);Gain of catalytic residue at S377 (P = 0.0464);Gain of catalytic residue at S377 (P = 0.0464);Gain of catalytic residue at S377 (P = 0.0464);.;Gain of catalytic residue at S377 (P = 0.0464);Gain of catalytic residue at S377 (P = 0.0464);Gain of catalytic residue at S377 (P = 0.0464);Gain of catalytic residue at S377 (P = 0.0464);Gain of catalytic residue at S377 (P = 0.0464);.;
MVP
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at