NM_000548.5:c.5115_5116dupCC

Variant names:

• chr16-2088093-A-ACC
• rs137853981
• NM_000548.5:c.5115_5116dupCC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000548.5(TSC2):​c.5115_5116dupCC​(p.Arg1706ProfsTer121) 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. R1706R) 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, single submitter P:1
• Conservation: PhyloP100: 0.201
• Publications: 0 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 12 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 16-2088093-A-ACC is Pathogenic according to our data. Variant chr16-2088093-A-ACC is described in ClinVar as Pathogenic. ClinVar VariationId is 1745431.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.5115_5116dupCC	p.Arg1706ProfsTer121	frameshift	Exon 40 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.5112_5113dupCC	p.Arg1705ProfsTer121	frameshift	Exon 40 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.5046_5047dupCC	p.Arg1683ProfsTer121	frameshift	Exon 39 of 41	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.5115_5116dupCC	p.Arg1706ProfsTer121	frameshift	Exon 40 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.5046_5047dupCC	p.Arg1683ProfsTer121	frameshift	Exon 39 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.4914_4915dupCC	p.Arg1639ProfsTer121	frameshift	Exon 38 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Nov 12, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5115_5116dupCC pathogenic mutation, located in coding exon 39 of the TSC2 gene, results from a duplication of CC at nucleotide position 5115, causing a translational frameshift with a predicted alternate stop codon (p.R1706Pfs*121). This frameshift occurs at the 3' terminus of TSC2, is not expected to trigger nonsense-mediated mRNA decay, and results in the elongation of the protein by 18 amino acids. This alteration was reported in a patient meeting clinical diagnostic criteria for tuberous sclerosis (Ambry Internal data), and other elongations of TSC2 that disrupt this region of the protein have been reported in the literature in patients with tuberous sclerosis (Jones AC et al. Hum. Mol. Genet. 1997 Nov;6(12):2155-61; Gilbert JR et al. Neurogenetics 1998 Aug;1(4):267-72; Jones AC et al. Am. J. Hum. Genet. 1999 May;64(5):1305-15; Au KS et al. Genet. Med. 2007 Feb;9(2):88-100). Based on the available evidence, this alteration is classified as a pathogenic mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.20

Splicing

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

Other links and lift over

dbSNP: rs137853981; hg19: chr16-2138094;