chr16-2084491-G-A

Position:

• chr16-2084491-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000548.5(TSC2):​c.4269G>A​(p.Leu1423Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00353 in 1,609,194 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0036 (25 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:24 O:1
• Conservation: PhyloP100: -0.290

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-2084491-G-A is Benign according to our data. Variant chr16-2084491-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 49289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2084491-G-A is described in Lovd as [Benign]. Variant chr16-2084491-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.29 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00284 (433/152352) while in subpopulation NFE AF= 0.00375 (255/68020). AF 95% confidence interval is 0.00337. There are 1 homozygotes in gnomad4. There are 211 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 433 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4269G>A	p.Leu1423Leu	synonymous_variant	34/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4269G>A	p.Leu1423Leu	synonymous_variant	34/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 433 AN: 152234 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.0758

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00374

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00375

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00264 AC: 630 AN: 238522 Hom.: 5 AF XY: 0.00292 AC XY: 380 AN XY: 130358

Gnomad AFR exome AF: 0.000540

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00513

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00224

Gnomad FIN exome AF: 0.00350

Gnomad NFE exome AF: 0.00357

Gnomad OTH exome AF: 0.00292

GnomAD4 exome AF: 0.00361 AC: 5252 AN: 1456842 Hom.: 25 Cov.: 33 AF XY: 0.00365 AC XY: 2648 AN XY: 724646

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.00120

Gnomad4 ASJ exome AF: 0.00453

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00225

Gnomad4 FIN exome AF: 0.00354

Gnomad4 NFE exome AF: 0.00405

Gnomad4 OTH exome AF: 0.00291

GnomAD4 genome AF: 0.00284 AC: 433 AN: 152352 Hom.: 1 Cov.: 34 AF XY: 0.00283 AC XY: 211 AN XY: 74500

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00374

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00470

Gnomad4 NFE AF: 0.00375

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00372 Hom.: 0

Bravo AF: 0.00275

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:24 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:8

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	TSC2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 05, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 23, 2016	Variant summary: The c.4269G>A (p.Leu1423=) in TSC2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.0023 (305/99578 chrs tested), including 2 homozygous occurrences. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000068). The variant of interest has been cited as Benign/Likely Benign by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 03, 2013	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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 15, 2014	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 19, 2022	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 22, 2017	p.Leu1423Leu in exon 34 of TSC2: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue and is not located w ithin the splice consensus sequence. It has been identified in 0.2% (737/265766) of chromosomes, including 4 homozygotes) and the highest allele frequency of 0 .5% in Ashkenazi Jewish by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org; dbSNP rs45438898) -

Tuberous sclerosis 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Tuberous sclerosis syndrome Benign:2 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 11, 2014	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 02, 2020	- -

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

Aug 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.72
DANN	Benign	0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs45438898; hg19: chr16-2134492; COSMIC: COSV104375925; COSMIC: COSV104375925;