rs137854307

chr16-2084639-AAG-A

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.4422_4423del(p.Arg1474SerfsTer49) variant causes a frameshift change involving the alteration of a non-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:2 O:2
• Conservation: PhyloP100: 2.21

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 16-2084639-AAG-A is Pathogenic according to our data. Variant chr16-2084639-AAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 49296.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084639-AAG-A is described in Lovd as [Pathogenic]. Variant chr16-2084639-AAG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.4422_4423del	p.Arg1474SerfsTer49	frameshift_variant	34/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.4422_4423del	p.Arg1474SerfsTer49	frameshift_variant	34/42	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:2 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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)	-	- -

Tuberous sclerosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 11, 2023

This sequence change creates a premature translational stop signal (p.Arg1474Serfs*49) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 10533067). ClinVar contains an entry for this variant (Variation ID: 49296). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2016

The c.4422_4423delAG pathogenic mutation, located in coding exon 33 of the TSC2 gene, results from a deletion of two nucleotides at nucleotide positions 4422 to 4423, causing a translational frameshift with a predicted alternate stop codon (p.R1474Sfs*49). This alteration has been has been reported in several individuals meeting clinical diagnostic criteria for tuberous sclerosis complex (TSC) and has been identified as both a de novo and an inherited mutation (Niida Y et al. Hum. Mutat., 1999;14:412-22; Dabora SL et al. Am. J. Hum. Genet., 2001 Jan;68:64-80; Lyczkowski DA et al. J. Child Neurol., 2007 Dec;22:1348-55; Chen CP et al. Taiwan J Obstet Gynecol, 2009 Sep;48:327-31). Of note, this alteration is designated as c.4420_4421delAG in published literature. 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)		0.010		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: rs137854307; hg19: chr16-2134640;