rs137854360

Positions:

• chr16-2048746-TACTG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000548.5(TSC2):​c.133_136del​(p.Leu45GlufsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC2 NM_000548.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.12

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2048746-TACTG-T is Pathogenic according to our data. Variant chr16-2048746-TACTG-T is described in ClinVar as [Pathogenic]. Clinvar id is 49151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2048746-TACTG-T is described in Lovd as [Pathogenic]. Variant chr16-2048746-TACTG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.133_136del	p.Leu45GlufsTer3	frameshift_variant	2/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.133_136del	p.Leu45GlufsTer3	frameshift_variant	2/42	5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jun 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 09, 2019	This sequence change creates a premature translational stop signal (p.Leu45Glufs*3) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with tuberous sclerosis complex (PMID: 16981987, 21510812). ClinVar contains an entry for this variant (Variation ID: 49151). Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 25, 2023

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16981987, 21510812, 36232477, 32005694, 32211034, 29476190) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2024

The c.133_136delCTGA pathogenic mutation, located in coding exon 1 of the TSC2 gene, results from a deletion of 4 nucleotides at nucleotide positions 133 to 136, causing a translational frameshift with a predicted alternate stop codon (p.L45Efs*3). The predicted stop codon occurs in the 5’ end of the TSC2 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNA decay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This variant has been identified in individuals meeting clinical diagnostic criteria for Tuberous sclerosis complex (TSC) (Hung CC et al. BMC Med Genet, 2006 Sep;7:72; Tsai TS et al. Genet Test Mol Biomarkers, 2011 Jun;15:415-21; Zhang N et al. Front Genet, 2020 Feb;11:575750), and has been reported as a de novo mutation in at least two patients diagnosed with TSC (Suspitsin EN et al. J Hum Genet, 2018 May;63:597-604; Ding Y et al. Front Genet, 2020 Mar;11:204). 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

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs137854360; hg19: chr16-2098747;