Variant rs137854128 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PM4_SupportingPP5

The NM_000548.5(TSC2):c.2459_2461del(p.Ile820del) variant causes a inframe deletion 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D817D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

TSC2
NM_000548.5 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1O:2

Conservation

PhyloP100: 7.95

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 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 16-2074294-ACAT-A is Pathogenic according to our data. Variant chr16-2074294-ACAT-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 49592.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, not_provided=2, Uncertain_significance=1, Likely_pathogenic=1}. Variant chr16-2074294-ACAT-A is described in Lovd as [Pathogenic]. Variant chr16-2074294-ACAT-A is described in Lovd as [Likely_pathogenic]. Variant chr16-2074294-ACAT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.2459_2461del	p.Ile820del	inframe_deletion	22/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.2459_2461del	p.Ile820del	inframe_deletion	22/42	5	NM_000548.5		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

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

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	This variant, c.2459_2461del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Ile820del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of tuberous sclerosis complex (PMID: 18302728, 21309039, 21520333; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 49592). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TSC2 function (PMID: 18302728, 21309039). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 19, 2021	This variant was identified as de novo (maternity and paternity confirmed). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 02, 2015	- -

Tuberous sclerosis syndrome

Other:2

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	Apr 06, 2011	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2019

Reported in the LOVD TSC2 database in several patients reported to have clinical features of TSC, and in two families variant was noted to be inherited from a parent with mild features of TSC; Reported in the published literature using alternate nomenclature as c.2476delATC (p.I820del) in a patient with tuberous sclerosis complex who also had a missense variant (R1772C) that did not affect TSC function (Nellist et al., 2008); Functional studies indicate variant destabilizes the TSC2 protein (Hoogeveen- Westerveld et al., 2011; Nellist et al., 2008); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15798777, 18302728, 21309039) -

Intellectual disability

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Diagnostic Laboratory, Strasbourg University Hospital

Sep 10, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing