16-2086325-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000548.5(TSC2):ā€‹c.4795G>Cā€‹(p.Val1599Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,658 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1599M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

4
9
6

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 4.70
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 4 ACMG points.

PM1
In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 284 pathogenic changes around while only 47 benign (86%) in NM_000548.5
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC2NM_000548.5 linkc.4795G>C p.Val1599Leu missense_variant 37/42 ENST00000219476.9 NP_000539.2 P49815-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkc.4795G>C p.Val1599Leu missense_variant 37/425 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
34
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460658
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
726634
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
34

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoSep 13, 2024The TSC2 c.4795G>C (p.Val1599Leu) variant has not been reported in individuals with TSC2-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 21, 2022Not 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) -
Tuberous sclerosis 2 Uncertain:1Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 23, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Isolated focal cortical dysplasia type II Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsNov 21, 2023- -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 27, 2024The p.V1599L variant (also known as c.4795G>C), located in coding exon 36 of the TSC2 gene, results from a G to C substitution at nucleotide position 4795. The valine at codon 1599 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, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.57
D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.42
D
MetaRNN
Uncertain
0.74
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.96
D
MutationAssessor
Uncertain
2.5
M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.80
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
0.62
Sift
Benign
0.14
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G
Benign
0.28
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen
0.99
D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4
0.59
MutPred
0.52
Loss of catalytic residue at V1599 (P = 0.1373);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.73
ClinPred
0.83
D
GERP RS
4.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.37
gMVP
0.73

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs772687631; hg19: chr16-2136326; API