rs45517150

Variant names:

• chr16-2060655-G-A
• rs45517150
• NM_000548.5:c.976-15G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-2060655-G-A
• chr16-2060655-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000548.5(TSC2):​c.976-15G>A 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:8 O:1
• Conservation: PhyloP100: 2.05

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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-2060655-G-A is Pathogenic according to our data. Variant chr16-2060655-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 49396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2060655-G-A is described in Lovd as [Pathogenic]. Variant chr16-2060655-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.976-15G>A		intron_variant	Intron 10 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.976-15G>A		intron_variant	Intron 10 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:4

Oct 02, 2021

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intronic variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 11068191, 10533066).The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 26540169, 11112665, PS4). It is not observed in the gnomAD v2.1.1 dataset (PM2). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.843, 3Cnet: 0.995, PP3). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 10 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 likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 10533066, 11112665, 21520333, 26540169). In at least one individual the variant was observed to be de novo. This variant is also known as IVS9-15G>A. ClinVar contains an entry for this variant (Variation ID: 49396). Studies have shown that this variant results in skipping of exon 11 (referred to as exon 10), but is expected to preserve the integrity of the reading-frame (PMID: 10533066, 11068191). For these reasons, this variant has been classified as Pathogenic. -

Aug 01, 2022

Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Sep 23, 2022

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been reported in more than 10 individuals with a clinical diagnosis or suspicion of tuberous sclerosis, including as de novo in at least one individual and in the mosaic state in another (Selected publications: Mayer 1999 PMID: 10533066; Dabora 2001 PMID: 11112665; Tyburczy 2015 PMID: 26540169; Wang 2021 PMID: 33278787). This variant is absent from large control databases but is present in ClinVar, with multiple laboratories classifying it as pathogenic (Variation ID: 49396). Transcriptional analyses demonstrated that this variant leads to two abnormal transcripts: one with the in-frame skipping of exon 11, and one with the activation of a cryptic splice acceptor in exon 11 that results in the deletion of 56 nucleotides, introducing a frameshift and premature stop codon (Mayer 1999 PMID: 10533066; Mayer 2000 PMID: 11068191). Loss of function variants are a known mechanism of disease for this gene (Rosset 2017 PMID: 28222202). In summary, this variant is classified as pathogenic. -

Oct 26, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Sep 19, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In vitro mRNA analysis indicates the c.976-15G>A variant leads aberrant splicing of exon 11 (Mayer et al., 2000); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 10533066, 11112665, 26540169, 17304050, 19369101, 28968464, 33278787, 18466115, 11068191) -

TSC2-related disorder Pathogenic:1

May 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC2 c.976-15G>A variant is predicted to interfere with splicing. In the literature this variant is also referred to as IVS9-15G>A. Based on available splicing prediction programs (Alamut Visual Plus v1.6.1), this variant creates a cryptic splice acceptor site. Functional studies have also shown that this variant leads to skipping of exon 10 and the creation of a cryptic splice acceptor in exon 10 (Mayer et al. 1999. PubMed ID: 10533066; Mayer et al. 2000. PubMed ID: 11068191). This variant has been reported in individuals with tuberous sclerosis complex (TSC) (Mayer et al. 1999. PubMed ID: 10533066; Dabora et al. 2000. PubMed ID: 11112665; Mayer et al. 2000. PubMed ID: 11068191; Tyburczy et al. 2015. PubMed ID: 26540169; Rosset et al. 2017. PubMed ID: 28968464). This variant has also been reported in TSC patients in the presumed mosaic state (allelic frequency <50%) (Tyburczy et al. 2015. PubMed ID: 26540169). This variant has also been reported in an individual with status epilepticus (Wang et al. 2020. PubMed ID: 33278787). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare, and is interpreted as pathogenic in ClinVar by multiple clinical laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/49396/). This variant is interpreted as pathogenic. -

Tuberous sclerosis syndrome Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	19
DANN	Benign	0.39

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.97		Position offset: 2
DS_AL_spliceai		0.79		Position offset: 15

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

Publications

LitVar

Other links and lift over

dbSNP: rs45517150; hg19: chr16-2110656;