16-2057459-C-T

Position:

• chr16-2057459-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_000548.5(TSC2):​c.848+281C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: -0.865

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2057459-C-T is Pathogenic according to our data. Variant chr16-2057459-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 49923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2057459-C-T is described in Lovd as [Pathogenic]. Variant chr16-2057459-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.848+281C>T		intron_variant		ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.848+281C>T		intron_variant		5	NM_000548.5	ENSP00000219476

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 03, 2022	Studies have shown that this variant results in a splicing defect and introduces a premature termination codon (PMID: 10533066, 11068191). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 49923). This variant is also known as IVS8+281C>T. This variant has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 10533066, 26540169; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Lymphangiomyomatosis Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Dec 21, 2018

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PS1. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 23, 2021

Non-canonical splice site variant demonstrated to result in loss-of-function; RNA studies indicate the variant activates a cryptic splice donor site in intron 9, leading to the addition of incorrect amino acids and an additional stop codon in exon 10 (Mayer et al., 1999; Mayer et al., 2000); In silico analysis supports a deleterious effect on splicing; No data available from ethnically-matched control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 19823873, 10533066, 11068191, 32860008, 26540169) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2019

The c.848+281C>T intronic pathogenic mutation results from a C to T substitution 281 nucleotides after coding exon 8 in the TSC2 gene. This mutation has been detected twice, once as a de novo occurrence, in individuals meeting diagnostic criteria for tuberous sclerosis complex (TSC) (Mayer K et al. Hum. Mutat., 1999;14:401-11; Tyburczy ME et al. PLoS Genet., 2015 Nov;11:e1005637). Functional studies performed at the RNA level showed this mutation creates a cryptic splice donor site that leads to the structural functionality of intron 8, resulting in the incorporation of a pseudoexon between exons 8 and 9, and ultimately resulting in a frameshift and premature protein truncation (Mayer K et al. Biochim. Biophys. Acta, 2000 Nov;1502:495-507). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.4
DANN	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.91		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs45517132; hg19: chr16-2107460;