NM_000548.5:c.5254C>T

Variant names:

• chr16-2088320-C-T
• rs45517414
• NM_000548.5:c.5254C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000548.5(TSC2):​c.5254C>T​(p.Gln1752*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q1752Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 NM_000548.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5 U:1 O:1
• Conservation: PhyloP100: 1.18
• Publications: 10 publications found

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]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 14 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2088320-C-T is Pathogenic according to our data. Variant chr16-2088320-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 49367.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.5254C>T	p.Gln1752*	stop_gained	Exon 41 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.5254C>T	p.Gln1752*	stop_gained	Exon 41 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2

Jul 15, 2021

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 56 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (Stenson et al., 2014); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 17304050, 27535533)

Dec 20, 2016

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tuberous sclerosis 2 Pathogenic:1 Uncertain:1

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gln1752*) in the TSC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 56 amino acid(s) of the TSC2 protein. 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: 49367). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Pathogenic:1

Jul 30, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 05, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1752* pathogenic mutation (also known as c.5254C>T), located in coding exon 40 of the TSC2 gene, results from a C to T substitution at nucleotide position 5254. This changes the amino acid from a glutamine to a stop codon within coding exon 40. This alteration occurs at the 3' terminus of theTSC2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 3% of the protein. However, premature stop codons are typically deleterious in nature. This variant was reported in individual(s) with features consistent with Tuberous sclerosis complex (Au KS et al. Genet Med, 2007 Feb;9:88-100; Luo C et al. Orphanet J Rare Dis, 2022 Jul;17:288). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Tuberous sclerosis syndrome Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	46
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MetaRNN	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationAssessor	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		1.2
PROVEAN	Benign	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.83
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs45517414; hg19: chr16-2138321;