rs137854141

chr16-2086814-CTT-Cchr16-2086814-CTT-CTchr16-2086814-CTT-CTTT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000548.5(TSC2):c.4934_4935del(p.Phe1645CysfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.95

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 16-2086814-CTT-C is Pathogenic according to our data. Variant chr16-2086814-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 49981.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2086814-CTT-C is described in Lovd as [Pathogenic]. Variant chr16-2086814-CTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.4934_4935del	p.Phe1645CysfsTer7	frameshift_variant	38/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.4934_4935del	p.Phe1645CysfsTer7	frameshift_variant	38/42	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:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Jun 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 23, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 25, 2017	This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Phe1645Cysfs*7) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported to segregate with tuberous sclerosis in 2 families (PMID: 9452050). It has also been reported as de novo in individuals affected with tuberous sclerosis and Wilms tumor (PMID: 21567926, 9452050), but paternity was not confirmed in these individuals. This variant is also known as 4882delTT in the literature. ClinVar contains an entry for this variant (Variation ID: 49981). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). -

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

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137854141; hg19: chr16-2136815;