16-2065562-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000548.5(TSC2):​c.1643G>C​(p.Arg548Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 32)

Consequence

TSC2
NM_000548.5 missense

Scores

1
12
6

Clinical Significance

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

Conservation

PhyloP100: 5.62
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.1643G>C p.Arg548Thr missense_variant Exon 16 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.1643G>C p.Arg548Thr missense_variant Exon 16 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1Benign:1
Nov 07, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 02, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Uncertain:1
Nov 30, 2023
All of Us Research Program, National Institutes of Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

TSC2: PM2 -

TSC2-related disorder Uncertain:1
Feb 06, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The TSC2 c.1643G>C variant is predicted to result in the amino acid substitution p.Arg548Thr. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome Uncertain:1
Jul 09, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R548T variant (also known as c.1643G>C), located in coding exon 15 of the TSC2 gene, results from a G to C substitution at nucleotide position 1643. The arginine at codon 548 is replaced by threonine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.13
CADD
Uncertain
24
DANN
Benign
0.96
DEOGEN2
Uncertain
0.50
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Uncertain
0.31
Eigen_PC
Uncertain
0.22
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.91
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Uncertain
0.48
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.35
D
MutationAssessor
Benign
1.2
L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.9
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
0.55
Sift
Benign
0.040
D;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G
Uncertain
0.028
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
0.99
D;.;.;.;D;D;.;.;D;P;.;.;.;.;.
Vest4
0.49
MutPred
0.33
Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);.;
MVP
0.89
ClinPred
0.78
D
GERP RS
5.6
Varity_R
0.20
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs748938385; hg19: chr16-2115563; API