Variant rs587778732 details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000548.5.

BP6

Variant 16-2082467-CTGCCAAGGA-G is Benign according to our data. Variant chr16-2082467-CTGCCAAGGA-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 135377.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=4, not_provided=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.3846_3855delinsG	p.Ser1282_Gly1285delinsArg	protein_altering_variant	32/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.3846_3855delinsG	p.Ser1282_Gly1285delinsArg	protein_altering_variant	32/42	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.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:8Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 21, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 13, 2023	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 17, 2019	The TSC2 c.3846_3855delinsG (p.Ser1282_Gly1285delinsArg) variant has been reported in the published literature in individuals with epilepsy and/or neurodevelopmental delay (PMID: 29655203 (2018)) and in an infant who fulfils the diagnostic criteria for Tuberous sclerosis complex (TSC) (PMID: 26703369 (2016)). The infant was reported to have an additional pathogenic variant in TSC2, suggesting the c.3846_3855delinsG variant may not be responsible for disease (PMID: 26703369 (2016)). An experimental study describes this variant as having no impact on TSC2 function (PMID: 26703369 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, we are unable to determine the clinical significance of this variant. -

not specified

Uncertain:1Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2024	Variant summary: TSC2 c.3846_3855delinsG (p.Ser1282_Gly1285delinsArg) results in an in-frame deletion-insertion that is predicted to delete/insert 4 amino acids from the protein and also cause changes in 1 amino acid. The variant allele was found at a frequency of 0.00013 in 281462 control chromosomes. The observed variant frequency is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. c.3846_3855delinsG has been reported in the literature in unspecified individual(s) affected with epilepsy and neurodevelopmental disorder (Lindy_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Tuberous Sclerosis Complex. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 29655203). ClinVar contains an entry for this variant (Variation ID: 135377). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 21, 2016	- -

Tuberous sclerosis syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Apr 08, 2021

The TSC2 c.3846_3855delinsG (p.Ser1282_Gly1285delinsArg) change is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). This change is predicted to delete four amino acids and replace them with an arginine while preserving the reading frame. Functional studies indicate that this variant does not affect TSC2 protein stability, the interaction between TSC1 and TSC2, or TSC complex-dependent inhibition of TORC1 activity (BS3; PMID: 26703369). This variant has been identified in a family who fulfills diagnostic criteria for TSC and also carries a definite TSC-causing variant (BP2; PMID: 26703369), as well as unaffected individuals (internal data). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS3, BP2, PM2_Supporting. -

TSC2-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 14, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 16, 2023

This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

rs587778732

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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