rs137854128

Variant names:

• chr16-2074294-ACAT-A
• rs137854128
• NM_000548.5:c.2459_2461delTCA

Your query was ambiguous. Multiple possible variants found:

• chr16-2074294-ACAT-A
• chr16-2074294-ACAT-ACATCAT

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_000548.5(TSC2):​c.2459_2461delTCA​(p.Ile820del) variant causes a disruptive 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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 disruptive_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1 O:2
• Conservation: PhyloP100: 7.95

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 11 ACMG points.

• 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 [Pathogenic]. Clinvar id is 49592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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 rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2459_2461delTCA	p.Ile820del	disruptive_inframe_deletion	Exon 22 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2459_2461delTCA	p.Ile820del	disruptive_inframe_deletion	Exon 22 of 42	5	NM_000548.5	ENSP00000219476.3

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: Pathogenic

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

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:2

Aug 19, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed). -

Nov 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; internal data). It has also been observed to segregate with disease in related individuals. Algorithms developed to predict the effect of variants on gene product 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. -

not provided Pathogenic:2

Aug 19, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 (PMID: 18302728); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15798777, 21520333, 21309039, 18302728, 32917966, 31440721) -

Mar 27, 2024

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in large, multi-ethnic general populations. (http://gnomad.broadinstitute.org) This variant has been identified in multiple unrelated individuals with clinical features associated with this gene, including individuals where it appears to occur de novo. In some published literature, this variant is referred to as c.2451_2453del. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 18302728, 21309039) -

Tuberous sclerosis syndrome Other:2

Apr 06, 2011

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Intellectual disability Uncertain:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs137854128; hg19: chr16-2124295;