Genetic Variant TSC2:c.5260-49C>T (chr16-2088397-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000548.5(TSC2):c.5260-49C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.11 in 1,612,040 control chromosomes in the GnomAD database, including 14,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 4060 hom., cov: 34)

Exomes 𝑓: 0.10 ( 10085 hom. )

Consequence

TSC2
NM_000548.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: -3.24

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 16-2088397-C-T is Benign according to our data. Variant chr16-2088397-C-T is described in ClinVar as [Benign]. Clinvar id is 49420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088397-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.395 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.5260-49C>T		intron_variant	Intron 41 of 41	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.5260-49C>T		intron_variant	Intron 41 of 41	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.185

AC:

28065

AN:

151944

Hom.:

4052

Cov.:

show subpopulations

Gnomad AFR

AF:

0.401

Gnomad AMI

AF:

0.118

Gnomad AMR

AF:

0.138

Gnomad ASJ

AF:

0.151

Gnomad EAS

AF:

0.000966

Gnomad SAS

AF:

0.0292

Gnomad FIN

AF:

0.121

Gnomad MID

AF:

0.212

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.167

GnomAD3 exomes

AF:

0.106

AC:

26485

AN:

249040

Hom.:

2432

AF XY:

0.100

AC XY:

13537

AN XY:

135240

show subpopulations

Gnomad AFR exome

AF:

0.407

Gnomad AMR exome

AF:

0.0838

Gnomad ASJ exome

AF:

0.142

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0284

Gnomad FIN exome

AF:

0.115

Gnomad NFE exome

AF:

0.103

Gnomad OTH exome

AF:

0.119

GnomAD4 exome

AF:

0.102

AC:

149391

AN:

1459978

Hom.:

10085

Cov.:

AF XY:

0.0993

AC XY:

72157

AN XY:

726318

show subpopulations

Gnomad4 AFR exome

AF:

0.411

Gnomad4 AMR exome

AF:

0.0910

Gnomad4 ASJ exome

AF:

0.142

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.0306

Gnomad4 FIN exome

AF:

0.112

Gnomad4 NFE exome

AF:

0.100

Gnomad4 OTH exome

AF:

0.116

GnomAD4 genome

AF:

0.185

AC:

28106

AN:

152062

Hom.:

4060

Cov.:

AF XY:

0.180

AC XY:

13390

AN XY:

74364

show subpopulations

Gnomad4 AFR

AF:

0.400

Gnomad4 AMR

AF:

0.138

Gnomad4 ASJ

AF:

0.151

Gnomad4 EAS

AF:

0.000968

Gnomad4 SAS

AF:

0.0290

Gnomad4 FIN

AF:

0.121

Gnomad4 NFE

AF:

0.102

Gnomad4 OTH

AF:

0.165

Alfa

AF:

0.147

Hom.:

468

Bravo

AF:

0.199

Asia WGS

AF:

0.0350

AC:

124

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 25% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 23. Only high quality variants are reported. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 03, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 20, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Polycystic kidney disease, adult type

Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis 2

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

BayesDel_noAF

Benign

-0.87

CADD

Benign

0.29

DANN

Benign

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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