rs137854144

Variant names:

• chr16-2071789-CAG-C
• rs137854144
• NM_000548.5:c.1959_1960delAG

Your query was ambiguous. Multiple possible variants found:

• chr16-2071789-CAG-C
• chr16-2071789-CAG-CAGAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000548.5(TSC2):​c.1959_1960delAG​(p.Gly654LeufsTer2) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R653R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC2 NM_000548.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 8.88
• Publications: 1 publications found

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]

TSC2 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 16-2071789-CAG-C is Pathogenic according to our data. Variant chr16-2071789-CAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 65311.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1959_1960delAG	p.Gly654LeufsTer2	frameshift_variant	Exon 19 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1959_1960delAG	p.Gly654LeufsTer2	frameshift_variant	Exon 19 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1454300 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 722796

African (AFR) AF: 0.00 AC: 0 AN: 33354

American (AMR) AF: 0.00 AC: 0 AN: 43982

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25870

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.00 AC: 0 AN: 85022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109214

Other (OTH) AF: 0.00 AC: 0 AN: 60096

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:3

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2013

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly654Leufs*2) 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 clinical features of tuberous sclerosis complex (PMID: 21811971). This variant is also known as c.1957-1958delAG. ClinVar contains an entry for this variant (Variation ID: 65311). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

May 13, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as c.1957-1958delAG due the use of alternative nomenclature in association with tuberous sclerosis complex in the published literature (Li et al., 2011); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21811971) -

Tuberous sclerosis syndrome Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.9
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137854144; hg19: chr16-2121790; COSMIC: COSV54767375; COSMIC: COSV54767375;