16-2088603-TTGTG-TTG

Position:

• chr16-2088603-TTGTG-TTG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PM4 PP5_Very_Strong

The NM_000548.5(TSC2):​c.5422_5423delTG​(p.Ter1808fs) variant causes a frameshift, stop lost 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 (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 frameshift, stop_lost
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1 O:1
• Conservation: PhyloP100: 9.64

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Stoplost variant in NM_000548.5 Downstream stopcodon found after 47 codons.
• PP5: Variant 16-2088603-TTG-T is Pathogenic according to our data. Variant chr16-2088603-TTG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 49859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088603-TTG-T is described in Lovd as [Pathogenic]. Variant chr16-2088603-TTG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.5422_5423delTG	p.Ter1808fs	frameshift_variant, stop_lost	42/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.5422_5423delTG	p.Ter1808fs	frameshift_variant, stop_lost	42/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this protein extension affects TSC2 function (PMID: 11781698). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This protein extension has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 11781698, 23389244; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change disrupts the translational stop signal of the TSC2 mRNA. It is expected to extend the length of the TSC2 protein by an uncertain number of additional amino acid residues. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jul 10, 2020	- -

Abnormal cerebral morphology Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

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- -

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)		0.0		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

Other links and lift over

dbSNP: rs137854027; hg19: chr16-2138604;