16-2088460-CGCCTACTCCAACCCCA-C

Position:

• chr16-2088460-CGCCTACTCCAACCCCA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_000548.5(TSC2):​c.5281_5296del​(p.Ser1761LeufsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.27

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 Likely_pathogenic. Variant got 8 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 12 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2088460-CGCCTACTCCAACCCCA-C is Pathogenic according to our data. Variant chr16-2088460-CGCCTACTCCAACCCCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 406134.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2088460-CGCCTACTCCAACCCCA-C is described in Lovd as [Pathogenic]. Variant chr16-2088460-CGCCTACTCCAACCCCA-C is described in Lovd as [Pathogenic]. Variant chr16-2088460-CGCCTACTCCAACCCCA-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.5281_5296del	p.Ser1761LeufsTer60	frameshift_variant	42/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.5281_5296del	p.Ser1761LeufsTer60	frameshift_variant	42/42	5	NM_000548.5	ENSP00000219476

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

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2017

This sequence change deletes 16 nucleotides in exon 42 of the TSC2 mRNA (c.5281_5296delTCCAACCCCAGCCTAC), causing a frameshift at codon 1761. This creates a premature translational stop signal in the last exon of the TSC2 mRNA (p.Ser1761Leufs*60). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 47 amino acids of the TSC2 protein. For these reasons, this variant has been classified as Pathogenic. 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 disease-causing de novo variants in individuals affected with TSC (PMID: 10205261, 9328481, 24789117), suggesting that frameshift variants affecting the very C-terminal of TSC2 impact protein function and cause disease. This variant has been reported in an individual with tuberous sclerosis complex (TSC) in the Leiden Open-source Variation Database (PMID: 21520333, 25498131). -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064792923; hg19: chr16-2138461;