rs878854118

chr16-2088451-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000548.5(TSC2):c.5266del(p.Glu1756ArgfsTer70) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E1756E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.09

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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 17 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2088451-CG-C is Pathogenic according to our data. Variant chr16-2088451-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 238080.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.5266del	p.Glu1756ArgfsTer70	frameshift_variant	42/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.5266del	p.Glu1756ArgfsTer70	frameshift_variant	42/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 10, 2019

This variant is not present in population databases (ExAC no frequency). For these reasons, this variant has been classified as Pathogenic. Functional studies using animal models have shown that the C-terminus of the TSC2 protein is involved in tumor suppression (PMID: 8799170, 17379185). Multiple frameshift variants, including c.5340_5371del (p.1784Alafs*?) and c.5405_5408dup (p.Phe1803Leufs*42) located downstream of this variant, have been reported as de novo disease-causing variants in individuals affected with tuberous sclerosis complex (PMID: 10205261, 9328481, 24789117). This suggests that frameshift variants affecting the very C-terminus of TSC2 impact protein function and cause disease. This variant has not been reported in the literature in individuals with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 238080). This sequence change deletes 1 nucleotide from exon 42 of the TSC2 mRNA (c.5266delG), causing a frameshift at codon 1756. This creates a premature translational stop signal in the last exon of the TSC2 mRNA (p.Glu1756Argfs*70). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acids of the TSC2 protein. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Mar 04, 2022

The TSC2 c.5266delG; p.Glu1756ArgfsTer70 variant (rs878854118), to our knowledge, is not reported in the medical literaturE. However, frameshift variants that occur downstream of this variant have been described in affected individuals and are considered pathogenic (Ding 2020, Lindy 2018, Liu 2018). The variant is listed in the ClinVar database (Variation ID: 238080) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the TSC2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated TSC2 protein. This region of TSC2 encodes the GAP domain, critical for tumor suppression (Jin 1996, Momose 2007). Based on available information, this variant is classified as likely pathogenic. References: Ding Y et al. Genotype and Phenotype Analysis of Chinese Children With Tuberous Sclerosis Complex: A Pediatric Cohort Study. Front Genet. 2020 Mar 10;11:204. PMID: 32211034. Jin F et al. Suppression of tumorigenicity by the wild-type tuberous sclerosis 2 (Tsc2) gene and its C-terminal region. Proc Natl Acad Sci U S A. 1996 Aug 20;93(17):9154-9. PMID: 8799170. Lindy AS et al. Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. Epilepsia. 2018 May;59(5):1062-1071. PMID: 29655203. Liu J et al. Novel and de novo mutations in pediatric refractory epilepsy. Mol Brain. 2018 Sep 5;11(1):48. PMID: 30185235 Jin F et al. Suppression of tumorigenicity by the wild-type tuberous sclerosis 2 (Tsc2) gene and its C- Momose S et al. N-terminal hamartin-binding and C-terminal GAP domain of tuberin can separate in vivo. Biochem Biophys Res Commun. 2007 May 11;356(3):693-8. PMID: 17379185. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: 4

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854118; hg19: chr16-2138452;