16-2079159-C-T

Position:

• chr16-2079159-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000548.5(TSC2):​c.3094C>T​(p.Arg1032*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 3.35

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2079159-C-T is Pathogenic according to our data. Variant chr16-2079159-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 49240.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2079159-C-T is described in Lovd as [Pathogenic]. Variant chr16-2079159-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.3094C>T	p.Arg1032*	stop_gained	27/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.3094C>T	p.Arg1032*	stop_gained	27/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 24, 2023	This premature translational stop signal has been observed in individual(s) with tuberous sclerosis (PMID: 10942116, 11112665, 21510812). This sequence change creates a premature translational stop signal (p.Arg1032*) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 49240). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jan 17, 2023	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2022	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 34849272, 25432535, 25281918, 10942116, 23254740, 34403804, 32313033) -

Tuberous sclerosis syndrome Pathogenic:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 30, 2023	Variant summary: TSC2 c.3094C>T (p.Arg1032X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 250626 control chromosomes. c.3094C>T has been reported in the literature in individuals affected with Tuberous Sclerosis Complex (e.g. Sudarshan_2021). These data indicate that the variant is likely associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (e.g. Huynh_2015). A cell line with this variant was reported to result in a loss of TSC2 protein expression compared to cell lines with wild-type TSC2. The following publications have been ascertained in the context of this evaluation (PMID: 25724664, 34849272). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 18, 2021

- -

TSC2-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 26, 2024

The TSC2 c.3094C>T variant is predicted to result in premature protein termination (p.Arg1032*). This variant has been reported in individuals with Tuberous Sclerosis Complex (Table 1, Jones et al. 2000. PubMed ID: 10942116; Table 1, Yang et al. 2014. PubMed ID: 25281918; Table 1, Reyna-Fabián et al. 2020. PubMed ID: 32313033; Low-level mosaic finding, Bąbol-Pokora et al. 2021. PubMed ID: 34403804). This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/49240/). Nonsense variants in TSC2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.97
GERP RS		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs45465195; hg19: chr16-2129160; COSMIC: COSV54758316; COSMIC: COSV54758316;