rs764725850
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000548.5(TSC2):c.2167A>C(p.Ile723Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/20 in silico tools predict a benign outcome for this variant. 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. I723V) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Consequence
TSC2
NM_000548.5 missense
NM_000548.5 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 1.02
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
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2023 | The p.I723L variant (also known as c.2167A>C), located in coding exon 19 of the TSC2 gene, results from an A to C substitution at nucleotide position 2167. The isoleucine at codon 723 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is not well 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
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
N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
PrimateAI
Benign
T
PROVEAN
Benign
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
Sift
Benign
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G
Benign
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen
B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4
MutPred
Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);.;Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);.;Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);Loss of methylation at K720 (P = 0.0675);.;
MVP
ClinPred
T
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
Publications
No publications associated with this variant yet.