16-2088140-G-T

Variant names:

• chr16-2088140-G-T
• rs45517399
• NM_000548.5:c.5160+1G>T

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.5160+1G>T variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.66
• 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: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 3.3, offset of 10, new splice context is: gggGTgggt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-2088140-G-T is Pathogenic according to our data. Variant chr16-2088140-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 49427.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.5160+1G>T		splice_donor intron	N/A	NP_000539.2
	TSC2	NM_001406663.1		c.5157+1G>T		splice_donor intron	N/A	NP_001393592.1
	TSC2	NM_001114382.3		c.5091+1G>T		splice_donor intron	N/A	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.5160+1G>T		splice_donor intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.5091+1G>T		splice_donor intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.4959+1G>T		splice_donor intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Dec 29, 2016

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5160+1 G>T splice site variant in the TSC2 gene destroys the canonical splice donor site for intron 40. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. It has been reported as a pathogenic variant in the TSC2 LOVD database (TSC2 LOVD). Additionally, many other splice variants have been reported in the Human Gene Mutation Database in association with tuberous sclerosis (Stenson et al., 2014). The c.5160+1 G>T variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, c.5160+1 G>T is interpreted to be a pathogenic variant.

Hereditary cancer-predisposing syndrome Pathogenic:1

May 14, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5160+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 39 of the TSC2 gene. This variant was reported in individuals with features consistent with tuberous sclerosis complex (Yang G et al. Clin Genet, 2017 May;91:764-768; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely 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
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	32
DANN	Uncertain	0.98
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.7
GERP RS		4.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.33		Position offset: 9
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs45517399; hg19: chr16-2138141;