rs137854116

Variant names:

• chr16-2072981-CAGGT-C
• rs137854250
• NM_000548.5:c.2355+2_2355+5delTAGG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000548.5(TSC2):​c.2355+2_2355+5delTAGG variant causes a splice donor, splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 splice_donor, splice_region, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:2
• Conservation: PhyloP100: 9.67

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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.02488938 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.2, offset of 3, new splice context is: gagGTcaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2072981-CAGGT-C is Pathogenic according to our data. Variant chr16-2072981-CAGGT-C is described in ClinVar as [Pathogenic]. Clinvar id is 12406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2072981-CAGGT-C is described in Lovd as [Pathogenic]. Variant chr16-2072981-CAGGT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2355+2_2355+5delTAGG		splice_donor_variant, splice_region_variant, intron_variant	Intron 21 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2354_2355+2delAGGT	p.Gln785ProfsTer43	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 21 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

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:4

Sep 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 27, 2023

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC2 c.2355+2_2355+5del variant results in a deletion at the consensus splice donor site, which may result in splicing defects. This variant has been identified in at least five unrelated individuals with a phenotype consistent with tuberous sclerosis complex, including in one in which it occurred de novo (PMID: 10205261; 10533067; 19259131; 28968464; 34403804). This variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. PCR analysis of cDNA from a patient with the c.2355+2_2355+5del variant demonstrated aberrant splicing that resulted in a premature stop codon (PMID: 19259131). Based on the available evidence, the c.2355+2_2355+5del variant is classified as pathogenic for tuberous sclerosis. -

Nov 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a splice site in intron 21 of the TSC2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Tuberous sclerosis (PMID: 10205261, 10533067, 19259131). In at least one individual the variant was observed to be de novo. This variant is also known as 2355+2delTAGG, c.2355+1_2355+4del, IVS20 + 1-4 delGTAG, 2373+2del4bp. ClinVar contains an entry for this variant (Variation ID: 12406). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 19259131). For these reasons, this variant has been classified as Pathogenic. -

Dec 03, 2014

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Other:2

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Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

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Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

not provided Pathogenic:1

Jan 19, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC2 c.2355+2_2355+5del variant (rs137854250) is reported in the literature in individuals affected with tuberous sclerosis complex (Babol-Pokora 2021, Le Caignec 2009, Niida 1999, Rosset 2017). This variant is reported in ClinVar (Variation ID: 12406). This variant is also absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 21, and in vitro functional analyses demonstrate novel cryptic donor splice site and the generation of a premature stop codon (Le Caignec 2009). Based on available information, this variant is considered to be pathogenic. References: Babol-Pokora K et al. A multistep approach to the genotype-phenotype analysis of Polish patients with tuberous sclerosis complex. Eur J Med Genet. 2021 Oct;64(10):104309. PMID: 34403804. Le Caignec C. Three independent mutations in the TSC2 gene in a family with tuberous sclerosis. Eur J Hum Genet. 2009 Sep;17(9):1165-70. PMID: 19259131. Niida Y et al. Analysis of both TSC1 and TSC2 for germline mutations in 126 unrelated patients with tuberous sclerosis. Hum Mutat. 1999;14(5):412-22. PMID: 10533067. Rosset C et al. Molecular analysis of TSC1 and TSC2 genes and phenotypic correlations in Brazilian families with tuberous sclerosis. PLoS One. 2017 Oct 2;12(10):e0185713. PMID: 28968464. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.47		Position offset: 9
DS_DL_spliceai		0.99		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: rs137854250; hg19: chr16-2122982;