rs137854397

Positions:

• chr16-2088311-CGGCTCCGCCAGCGGGTAGGGAATATGG-C
• chr16-2088311-CGGCTCCGCCAGCGGGTAGGGAATATGG-CGGCTCCGCCAGCGGGTAGGGAATATGGGGCTCCGCCAGCGGGTAGGGAATATGG

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_Moderate PM2 PP3 PP5_Very_Strong

The NM_000548.5(TSC2):​c.5252_5259+19del variant causes a splice donor, splice donor 5th base, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R1749R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 NM_000548.5 splice_donor, splice_donor_5th_base, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 9.04

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 13 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.018067846 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.3, offset of 30, new splice context is: cggGTgtgt. 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
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 16-2088311-CGGCTCCGCCAGCGGGTAGGGAATATGG-C is Pathogenic according to our data. Variant chr16-2088311-CGGCTCCGCCAGCGGGTAGGGAATATGG-C is described in ClinVar as [Pathogenic]. Clinvar id is 49366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088311-CGGCTCCGCCAGCGGGTAGGGAATATGG-C is described in Lovd as [Pathogenic]. Variant chr16-2088311-CGGCTCCGCCAGCGGGTAGGGAATATGG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.5252_5259+19del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	41/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.5252_5259+19del		splice_donor_variant, splice_donor_5th_base_variant, coding_sequence_variant, intron_variant	41/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 34

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

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 03, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 16, 2023	This variant results in the deletion of part of exon 41 (c.5252_5252+19) of the TSC2 gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with tuberous sclerosis complex (PMID: 11112665, 21520333, 25498131). ClinVar contains an entry for this variant (Variation ID: 49366). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). This variant disrupts a region of the TSC2 protein in which other variant(s) (p.Ser1761Leufs*60) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 27, 2020

Deletions involving coding exons of this gene are a known mechanism of disease (Stenson et al., 2014); Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 27406250, 11112665, 16981987) -

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs137854397; hg19: chr16-2138312;