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rs137854128

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM4_SupportingPP3PP5

The NM_000548.5(TSC2):c.2459_2461del(p.Ile820del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. 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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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
PM4
Nonframeshift variant in NON repetitive region in NM_000548.5. Strenght limited to Supporting due to length of the change: 1aa.
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
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: {Uncertain_significance=1, Pathogenic=3, Likely_pathogenic=1, not_provided=2}. 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
TSC2NM_000548.5 linkuse as main transcriptc.2459_2461del p.Ile820del inframe_deletion 22/42 ENST00000219476.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.2459_2461del p.Ile820del inframe_deletion 22/425 NM_000548.5 P49815-1

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
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 submitterclinical testingInvitaeJan 21, 2024This 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. -
Likely pathogenic, criteria provided, single submitterclinical testingAthena Diagnostics IncSep 02, 2015- -
Pathogenic, criteria provided, single submitterclinical testingInstitute of Human Genetics, University of Leipzig Medical CenterAug 19, 2021This variant was identified as de novo (maternity and paternity confirmed). -
Tuberous sclerosis syndrome Other:2
not provided, no classification providedcurationTuberous sclerosis database (TSC2)Apr 06, 2011- -
not provided, no classification providedcurationTuberous sclerosis database (TSC2)-- -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingGeneDxNov 18, 2019Reported 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 submitterclinical testingDiagnostic Laboratory, Strasbourg University HospitalSep 10, 2020- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

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

Other links and lift over

dbSNP: rs137854128; hg19: chr16-2124295; API