16-2088217-A-C

Position:

• chr16-2088217-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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:17 O:1
• Conservation: PhyloP100: -2.26

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]

ACMG classification

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	UniProt
TSC2	NM_000548.5	c.5161-10A>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.5161-10A>C		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.299 AC: 45467 AN: 151892 Hom.: 9050 Cov.: 33

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

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.: 35 AF XY: 0.205 AC XY: 148942 AN XY: 726648

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.: 33 AF XY: 0.295 AC XY: 21932 AN XY: 74304

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:17 Other:1

Revision: criteria provided, multiple submitters, no conflicts

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:1 Other: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

Other links and lift over

dbSNP: rs1800718; hg19: chr16-2138218; COSMIC: COSV99237259; COSMIC: COSV99237259;