rs757579310

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000548.5(TSC2):​c.4286C>G​(p.Ala1429Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 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. A1429S) has been classified as Benign.

Frequency

Genomes: not found (cov: 34)

Consequence

TSC2
NM_000548.5 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.442
Variant links:
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1152879).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.4286C>G p.Ala1429Gly missense_variant Exon 34 of 42 ENST00000219476.9 NP_000539.2 P49815-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkc.4286C>G p.Ala1429Gly missense_variant Exon 34 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
Cov.:
33
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
Aug 11, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is not present in population databases (gnomAD no frequency). 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: 1427263). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1429 of the TSC2 protein (p.Ala1429Gly). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.072
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.070
CADD
Benign
15
DANN
Benign
0.73
DEOGEN2
Benign
0.38
T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.15
N
LIST_S2
Benign
0.76
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Uncertain
0.20
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.59
T
MutationAssessor
Benign
1.5
L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.37
T
PROVEAN
Benign
-0.68
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
0.54
Sift
Benign
0.51
T;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Benign
0.37
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen
0.044
B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4
0.18
MutPred
0.21
Gain of loop (P = 0.0166);.;.;.;.;.;.;Gain of loop (P = 0.0166);.;.;.;.;.;.;.;
MVP
0.93
ClinPred
0.089
T
GERP RS
2.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.076
gMVP
0.20

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2134509; API