rs137854071

Positions:

• chr16-2071906-TC-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.2071del​(p.Arg691AlafsTer7) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. F690F) has been classified as Likely benign. 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:1
• Conservation: PhyloP100: 0.473

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 16-2071906-TC-T is Pathogenic according to our data. Variant chr16-2071906-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 49715.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071906-TC-T is described in Lovd as [Likely_pathogenic]. Variant chr16-2071906-TC-T is described in Lovd as [Pathogenic]. Variant chr16-2071906-TC-T is described in Lovd as [Pathogenic]. Variant chr16-2071906-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.2071del	p.Arg691AlafsTer7	frameshift_variant	19/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2071del	p.Arg691AlafsTer7	frameshift_variant	19/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 12, 2021

This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg691Alafs*7) 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 premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 9463313, 28968464). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49715). This variant is also known as del1bp, 690PheFSr697X. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Mar 05, 2018

c.2071delC: p.Arg691AlafsX7 in exon 19 in the TSC2 gene (NM_000548.3). The normal sequence with the base(s) that are deleted in braces is: CTTC{C}GCGT. The c.2071delC pathogenic variant in the TSC2 gene has been reported previously in association with tuberous sclerosis complex (Au et al., 1998; Ali et al., 2005; TSC2 LOVD). The deletion causes a frameshift starting with codon Arginine 691, changes this amino acid to an Alanine residue and creates a premature Stop codon at position 7 of the new reading frame, denoted p.Arg691AlafsX7. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.2071delCvariant is not observed in large population cohorts (Lek et al., 2016). Therefore, the presence of c.2071delC is consistent with the diagnosis of tuberous sclerosis complex in this individual. -

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: rs137854071; hg19: chr16-2121907;