rs137854175

Positions:

• chr16-2084997-TCAAA-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000548.5(TSC2):​c.4544_4547del​(p.Asn1515SerfsTer60) variant causes a frameshift 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 (★★). 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:8 O:2
• Conservation: PhyloP100: 9.18

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2084997-TCAAA-T is Pathogenic according to our data. Variant chr16-2084997-TCAAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 49304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084997-TCAAA-T is described in Lovd as [Pathogenic]. Variant chr16-2084997-TCAAA-T is described in Lovd as [Pathogenic]. Variant chr16-2084997-TCAAA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4544_4547del	p.Asn1515SerfsTer60	frameshift_variant	35/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4544_4547del	p.Asn1515SerfsTer60	frameshift_variant	35/42	5	NM_000548.5	ENSP00000219476

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:8 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jun 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 15, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49304). This premature translational stop signal has been observed in individuals with tuberous sclerosis (PMID: 9302281, 11112665, 12111193, 15595939, 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn1515Serfs*60) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 19, 2014	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2016	The c.4544_4547delACAA pathogenic variant in the TSC2 gene has been reported previously multiple times in association with tuberous sclerosis complex (Maheshwar et al., 1997, Ali et al., 2005, TSC2 LOVD). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The deletion causes a frameshift starting with codon Asparagine 1515, changes this amino acid to a Serine residue and creates a premature Stop codon at position 60 of the new reading frame, denoted p.Asn1515SerfsX60. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 21, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 21, 2023	PP4, PM2, PS4_moderate, PVS1 -

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)	-	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2017

The c.4544_4547delACAA pathogenic mutation, located in coding exon 34 of the TSC2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4544 to 4547, causing a translational frameshift with a predicted alternate stop codon (p.N1515Sfs*60). This pathogenic mutation has been reported in multiple individuals diagnosed with tuberous sclerosis complex (TSC) (Ali M et al. Acta Neurol. Scand. 2005 Jan;111:54-63; Au KS et al. Genet. Med., 2007 Feb;9:88-100). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137854175; hg19: chr16-2134998;