rs137854250

chr16-2072981-CAGGT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1_Moderate PP3 PP5_Very_Strong

The NM_000548.5(TSC2):c.2355+2_2355+5del variant causes a splice donor, coding sequence change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q785Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 splice_donor, coding_sequence
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 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 11 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.024705015 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.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• 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/exons	MANE	UniProt
TSC2	NM_000548.5	c.2355+2_2355+5del		splice_donor_variant, coding_sequence_variant	21/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2355+2_2355+5del		splice_donor_variant, coding_sequence_variant	21/42	5	NM_000548.5

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:4 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 27, 2023	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 disrupted 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 introduces a premature termination codon (PMID: 19259131). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 27, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 03, 2014	- -

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)		0.99		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;