rs137854146

chr16-2085312-GAGA-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000548.5(TSC2):c.4655_4657del(p.Glu1552del) variant causes a inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G1551G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 6.58

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 13 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 15 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000548.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 16-2085312-GAGA-G is Pathogenic according to our data. Variant chr16-2085312-GAGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 49310.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2085312-GAGA-G is described in Lovd as [Pathogenic]. Variant chr16-2085312-GAGA-G is described in Lovd as [Likely_pathogenic]. Variant chr16-2085312-GAGA-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.4655_4657del	p.Glu1552del	inframe_deletion	36/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.4655_4657del	p.Glu1552del	inframe_deletion	36/42	5	NM_000548.5

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:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:3

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	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 26, 2023	Experimental studies have shown that this variant affects TSC2 function (PMID: 22903760). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 49310). This variant is also known as 4654_4656delGAA. This variant has been observed in individual(s) with tuberous sclerosis (PMID: 11112665, 22903760, 23389244). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This variant, c.4655_4657del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Glu1552del), but otherwise preserves the integrity of the reading frame. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2021

The c.4655_4657delAAG variant (also known as p.E1552del) is located in coding exon 35 of the TSC2 gene. This variant results from an in-frame AAG deletion at nucleotide positions 4655 to 4657. This results in the in-frame deletion of a glutamic acid at codon 1552. This alteration has been identified in numerous individuals with clinical features associated with tuberous sclerosis (Roberts PS et al. Hum Genet, 2002 Jul;111:96-101; Niida Y et al. J Hum Genet, 2013 Apr;58:216-25). An in vitro functional assay showed that this variant is deleterious compared to wild-type (Hoogeveen-Westerveld M et al. Hum Mutat 2013 Jan;34(1):167-75). Of note, this alteration is also described in the literature as c.4654_4656delGAA. This amino acid position is well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

-

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs137854146; hg19: chr16-2135313;