16-2085322-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000548.5(TSC2):c.4662G>C(p.Gln1554His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q1554P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Consequence

TSC2
NM_000548.5 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Uncertain significance no assertion criteria provided U:1O:1

Conservation

PhyloP100: 9.66

Publications

3 publications found

Variant links:

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

TSC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 39 uncertain in NM_000548.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-2085321-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 49866.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.4662G>C	p.Gln1554His	missense_variant, splice_region_variant	Exon 36 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.4662G>C	p.Gln1554His	missense_variant, splice_region_variant	Exon 36 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TSC2-related disorder

Uncertain:1

Feb 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TSC2 c.4662G>C variant is predicted to result in the amino acid substitution p.Gln1554His. This variant occurs at the final nucleotide position of exon 36 and splicing prediction programs predict a splicing defect at the consensus donor site (SpliceAI, Jaganathan K, et al. 2019. PubMed ID: 30661751). This variant was reported as probably pathogenic in an individual with suspected tuberous sclerosis complex (TSC); however, detailed clinical information was not provided (Table S2, Hoogeveen-Westerveld et al. 2013. PubMed ID: 22903760). In addition, functional analyses of this variant showed that it led to an increased but "intermediate" effect when compared to wild type and a known pathogenic TSC2 variant (Table S1, Hoogeveen-Westerveld et al. 2013. PubMed ID: 22903760). This variant has not been reported in large population database, indicating this variant is rare. Of note, a different nucleotide variant (c.4662G>T) leading to the same amino acid change (p. Gln1554His) was reported as de novo in a patient with TSC (Rendtorff et al. 2005. PubMed ID: 16114042). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;.;.;.;.;.;.;.;.;.;.;.;D;.;D

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.95

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

H;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

9.7

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-4.6

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Sift4G

Uncertain

0.0020

D;.;.;D;.;D;.;.;D;D;.;.;.;.;D

Vest4

0.87

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.95

gMVP

0.97

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.96

SpliceAI score (max)

0.85

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.58

Position offset: 23

DS_DL_spliceai

0.85

Position offset: 0

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over