Genetic Variant TSC2:c.1600-39C>T (chr16-2065480-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.1600-39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.087 in 1,502,856 control chromosomes in the GnomAD database, including 6,350 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 507 hom., cov: 31)

Exomes 𝑓: 0.089 ( 5843 hom. )

Consequence

TSC2
NM_000548.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3O:1

Conservation

PhyloP100: 0.549

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=-0.82).

BP6

Variant 16-2065480-C-T is Benign according to our data. Variant chr16-2065480-C-T is described in ClinVar as [Benign]. Clinvar id is 49695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2065480-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.1600-39C>T		intron_variant	Intron 15 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.1600-39C>T		intron_variant	Intron 15 of 41	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.0732

AC:

11031

AN:

150744

Hom.:

506

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0262

Gnomad AMI

AF:

0.0828

Gnomad AMR

AF:

0.0733

Gnomad ASJ

AF:

0.148

Gnomad EAS

AF:

0.000775

Gnomad SAS

AF:

0.0271

Gnomad FIN

AF:

0.129

Gnomad MID

AF:

0.130

Gnomad NFE

AF:

0.0972

Gnomad OTH

AF:

0.0881

GnomAD3 exomes

AF:

0.0737

AC:

18357

AN:

248940

Hom.:

959

AF XY:

0.0746

AC XY:

10056

AN XY:

134758

show subpopulations

Gnomad AFR exome

AF:

0.0248

Gnomad AMR exome

AF:

0.0483

Gnomad ASJ exome

AF:

0.139

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0255

Gnomad FIN exome

AF:

0.127

Gnomad NFE exome

AF:

0.0967

Gnomad OTH exome

AF:

0.0983

GnomAD4 exome

AF:

0.0886

AC:

119737

AN:

1352024

Hom.:

5843

Cov.:

AF XY:

0.0872

AC XY:

59042

AN XY:

677172

show subpopulations

Gnomad4 AFR exome

AF:

0.0249

Gnomad4 AMR exome

AF:

0.0522

Gnomad4 ASJ exome

AF:

0.142

Gnomad4 EAS exome

AF:

0.0000520

Gnomad4 SAS exome

AF:

0.0289

Gnomad4 FIN exome

AF:

0.125

Gnomad4 NFE exome

AF:

0.0972

Gnomad4 OTH exome

AF:

0.0862

GnomAD4 genome

AF:

0.0732

AC:

11040

AN:

150832

Hom.:

507

Cov.:

AF XY:

0.0730

AC XY:

5371

AN XY:

73558

show subpopulations

Gnomad4 AFR

AF:

0.0263

Gnomad4 AMR

AF:

0.0732

Gnomad4 ASJ

AF:

0.148

Gnomad4 EAS

AF:

0.000776

Gnomad4 SAS

AF:

0.0274

Gnomad4 FIN

AF:

0.129

Gnomad4 NFE

AF:

0.0973

Gnomad4 OTH

AF:

0.0872

Alfa

AF:

0.0907

Hom.:

154

Bravo

AF:

0.0681

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 12, 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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.82

CADD

Benign

6.3

DANN

Benign

0.39

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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