rs1800718

Positions:

Variant summary

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

The NM_000548.5(TSC2):c.5161-10A>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.218 in 1,612,766 control chromosomes in the GnomAD database, including 45,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.30 ( 9079 hom., cov: 33)

Exomes 𝑓: 0.21 ( 36010 hom. )

Consequence

TSC2
NM_000548.5 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00002236

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17O:1

Conservation

PhyloP100: -2.26

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=-0.92).

BP6

Variant 16-2088217-A-C is Benign according to our data. Variant chr16-2088217-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 49431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088217-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.5161-10A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.5161-10A>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000548.5	ENSP00000219476		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.299

AC:

45467

AN:

151892

Hom.:

9050

Cov.:

show subpopulations

Gnomad AFR

AF:

0.558

Gnomad AMI

AF:

0.150

Gnomad AMR

AF:

0.213

Gnomad ASJ

AF:

0.244

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0966

Gnomad FIN

AF:

0.260

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.211

Gnomad OTH

AF:

0.266

GnomAD3 exomes

AF:

0.200

AC:

50039

AN:

250654

Hom.:

6816

AF XY:

0.193

AC XY:

26228

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.560

Gnomad AMR exome

AF:

0.130

Gnomad ASJ exome

AF:

0.250

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0970

Gnomad FIN exome

AF:

0.258

Gnomad NFE exome

AF:

0.213

Gnomad OTH exome

AF:

0.212

GnomAD4 exome

AF:

0.209

AC:

305591

AN:

1460756

Hom.:

36010

Cov.:

AF XY:

0.205

AC XY:

148942

AN XY:

726648

show subpopulations

Gnomad4 AFR exome

AF:

0.565

Gnomad4 AMR exome

AF:

0.139

Gnomad4 ASJ exome

AF:

0.254

Gnomad4 EAS exome

AF:

0.000327

Gnomad4 SAS exome

AF:

0.0992

Gnomad4 FIN exome

AF:

0.255

Gnomad4 NFE exome

AF:

0.213

Gnomad4 OTH exome

AF:

0.222

GnomAD4 genome

AF:

0.300

AC:

45546

AN:

152010

Hom.:

9079

Cov.:

AF XY:

0.295

AC XY:

21932

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.559

Gnomad4 AMR

AF:

0.212

Gnomad4 ASJ

AF:

0.244

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.0963

Gnomad4 FIN

AF:

0.260

Gnomad4 NFE

AF:

0.211

Gnomad4 OTH

AF:

0.263

Alfa

AF:

0.232

Hom.:

2551

Bravo

AF:

0.308

Asia WGS

AF:

0.0850

AC:

296

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 33% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 31. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	5161-10A>C in intron 40 of TSC2: This variant is not expected to have clinical s ignificance because it has been identified in 45.7% (2010/4396) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs1800718). -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Tuberous sclerosis 2

Benign:5

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2016	Variant summary: The TSC2 c.5161-10A>C variant involves the alteration of a non-conserved intronic nucleotide with 5/5 splice prediction tools predicting no significant impact on splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 24902/120464 (3635 homozygotes, 1/4), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic TSC2 variant of 1/14534 (0.0000688), suggesting this variant is likely a benign polymorphism. In addition, multiple reputable clinical laboratories cite the variant as "benign/likely benign." Therefore, the variant of interest has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Tuberous sclerosis syndrome

Benign:1Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.072

DANN

Benign

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000022

dbscSNV1_RF

Benign

0.0020

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