chr16-2079657-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_000548.5(TSC2):c.3385C>T(p.Arg1129Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000502 in 1,594,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 2.81

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.823

BS2

High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.3385C>T	p.Arg1129Cys	missense_variant	Exon 29 of 42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.3385C>T	p.Arg1129Cys	missense_variant	Exon 29 of 42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000188

AC:

AN:

212436

Hom.:

AF XY:

0.00000869

AC XY:

AN XY:

115132

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000324

Gnomad ASJ exome

AF:

0.000108

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000566

Gnomad NFE exome

AF:

0.0000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000485

AC:

AN:

1442618

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

716042

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000237

Gnomad4 ASJ exome

AF:

0.0000388

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000198

Gnomad4 NFE exome

AF:

0.00000362

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: TSC2 c.3385C>T (p.Arg1129Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.9e-05 in 212436 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3385C>T has been reported in the literature in at least one individual affected with Tuberous Sclerosis Complex (e.g., Meng_2021). This report does not provide unequivocal conclusions about association of the variant with Tuberous Sclerosis Complex. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 32917966). ClinVar contains an entry for this variant (Variation ID: 406032). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Tuberous sclerosis syndrome

Uncertain:1

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 1129 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with clinically suspected tuberous sclerosis complex (PMID: 32917966). This variant has been identified in 4/212436 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

TSC2-related disorder

Uncertain:1

Jan 19, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TSC2 c.3385C>T variant is predicted to result in the amino acid substitution p.Arg1129Cys. This variant has been reported in and individual with cortical dysplasia and tuberous sclerosis complex-associated neuropsychiatric disorder (Table S1, ID: NP15D2345, Meng et al. 2021. PubMed ID: 32917966). It has also been reported in an individual with a pancreatic neuroendocrine tumor (Midie et al. 2022. PubMed ID: 36140756). This variant is reported in 4 of ~212,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/16-2129658-C-T) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/406032/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R1129C variant (also known as c.3385C>T), located in coding exon 28 of the TSC2 gene, results from a C to T substitution at nucleotide position 3385. The arginine at codon 1129 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in 1/347 Chinese patients with clinically suspected tuberous sclerosis complex (TSC) and called a variant of uncertain significance by the authors (Meng Y et al. J Hum Genet, 2021 Mar;66:227-236). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 2

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

D;.;.;.;.;.;.;.;.;.;.;.;T;.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.82

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

MetaSVM

Uncertain

0.76

MutationAssessor

Uncertain

2.3

M;.;.;.;.;.;.;.;.;M;.;.;.;.;.

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.9

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

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

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

Sift4G

Pathogenic

0.0010

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

Polyphen

1.0

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

Vest4

0.86

MutPred

0.38

Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);.;.;.;.;Gain of sheet (P = 0.0149);.;Gain of sheet (P = 0.0149);.;.;.;.;.;

MVP

0.98

ClinPred

0.94

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.39

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over