16-2085280-C-G

Variant names:

• chr16-2085280-C-G
• rs45455897
• NM_000548.5:c.4620C>G

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.4620C>G​(p.Tyr1540*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Y1540Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: TSC2 NM_000548.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: -2.73
• Publications: 9 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 16-2085280-C-G is Pathogenic according to our data. Variant chr16-2085280-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 49849.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.4620C>G	p.Tyr1540*	stop_gained	Exon 36 of 42	NP_000539.2
	TSC2	NM_001406663.1		c.4617C>G	p.Tyr1539*	stop_gained	Exon 36 of 42	NP_001393592.1
	TSC2	NM_001114382.3		c.4551C>G	p.Tyr1517*	stop_gained	Exon 35 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.4620C>G	p.Tyr1540*	stop_gained	Exon 36 of 42	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.4551C>G	p.Tyr1517*	stop_gained	Exon 35 of 41	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.4419C>G	p.Tyr1473*	stop_gained	Exon 34 of 40	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:1

Feb 17, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 49849). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis (PMID: 20633017, 24271014). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr1540*) 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).

TSC2-related disorder Pathogenic:1

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The TSC2 c.4620C>G variant is predicted to result in premature protein termination (p.Tyr1540*). This variant was reported in patients with Tuberous sclerosis (Table 1 in Qin W et al 2010. PubMed ID: 20633017; Table 2 in Tyburczy ME et al 2013. PubMed ID: 24271014). Of note, another nonsense variant affecting the same amino acid (c.4620C>A, p.Tyr1540*) has also been reported to be pathogenic for Tuberous sclerosis (HGMD database, Reyna-Fabián. 2020. PubMed ID: 32313033). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in TSC2 are expected to be pathogenic. This variant is interpreted as pathogenic.

Tuberous sclerosis syndrome Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	25
DANN	Benign	0.93
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.31	N
PhyloP100		-2.7
Vest4		0.91
GERP RS		-8.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs45455897; hg19: chr16-2135281;