rs137854261

Positions:

• chr16-2086790-CAAG-C

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.4912_4914del​(p.Lys1638del) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K1637K) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 9.24

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 mutagenesis_site Abolishes GAP activity. (size 2) in uniprot entity TSC2_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) 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 16-2086790-CAAG-C is Pathogenic according to our data. Variant chr16-2086790-CAAG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 49893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2086790-CAAG-C is described in Lovd as [Pathogenic]. Variant chr16-2086790-CAAG-C is described in Lovd as [Pathogenic]. Variant chr16-2086790-CAAG-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4912_4914del	p.Lys1638del	inframe_deletion	38/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4912_4914del	p.Lys1638del	inframe_deletion	38/42	5	NM_000548.5	ENSP00000219476

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/Likely pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 20, 2014	Not found in the total gnomAD dataset. Found in multiple de novo cases. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2020	Reported multiple times as a pathogenic variant is association with tuberous sclerosis complex (Au et al., 2007, Qin et al, 2010, vanEeghen et al., 2013; TSC2 LOVD); Not observed in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32555378, 22867869, 20165957, 17304050, 31855466) -

Tuberous sclerosis 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 16, 2023	This variant, c.4912_4914del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Lys1638del), 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 individual(s) with tuberous sclerosis complex (PMID: 17304050, 20165957, 21520333, 22867869). In at least one individual the variant was observed to be de novo. This variant is also known as c.4909_4911delAAG. ClinVar contains an entry for this variant (Variation ID: 49893). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jul 10, 2020	- -

Tuberous sclerosis syndrome Other:2

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
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)		0.010		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: rs137854261; hg19: chr16-2136791;