rs1800748

Positions:

• chr16-2058754-A-G
• chr16-2058754-A-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000548.5(TSC2):​c.856A>G​(p.Met286Val) variant causes a missense change. The variant allele was found at a frequency of 0.00109 in 1,582,982 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M286T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (13 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20 O:2
• Conservation: PhyloP100: 4.60

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 -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 6 benign, 16 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.00816381).
• BP6: Variant 16-2058754-A-G is Benign according to our data. Variant chr16-2058754-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 50009.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2058754-A-G is described in Lovd as [Benign]. Variant chr16-2058754-A-G is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00112 (170/152274) while in subpopulation EAS AF= 0.021 (109/5190). AF 95% confidence interval is 0.0178. There are 3 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 170 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.856A>G	p.Met286Val	missense_variant	10/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.856A>G	p.Met286Val	missense_variant	10/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152156 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0208

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00186 AC: 374 AN: 200760 Hom.: 5 AF XY: 0.00177 AC XY: 190 AN XY: 107340

Gnomad AFR exome AF: 0.0000789

Gnomad AMR exome AF: 0.000105

Gnomad ASJ exome AF: 0.000112

Gnomad EAS exome AF: 0.0187

Gnomad SAS exome AF: 0.000582

Gnomad FIN exome AF: 0.000223

Gnomad NFE exome AF: 0.000637

Gnomad OTH exome AF: 0.00173

GnomAD4 exome AF: 0.00108 AC: 1552 AN: 1430708 Hom.: 13 Cov.: 32 AF XY: 0.00108 AC XY: 766 AN XY: 708534

Gnomad4 AFR exome AF: 0.0000905

Gnomad4 AMR exome AF: 0.0000761

Gnomad4 ASJ exome AF: 0.0000786

Gnomad4 EAS exome AF: 0.0181

Gnomad4 SAS exome AF: 0.000743

Gnomad4 FIN exome AF: 0.000196

Gnomad4 NFE exome AF: 0.000619

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00112 AC: 170 AN: 152274 Hom.: 3 Cov.: 33 AF XY: 0.00120 AC XY: 89 AN XY: 74456

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0210

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00144 Hom.: 0

Bravo AF: 0.00126

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000699 AC: 6

ExAC AF: 0.00162 AC: 195

Asia WGS AF: 0.00260 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:20 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 26, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	Met286Val in exon 10 of TSC2: This variant is not expected to have clinical sign ificance because it has been identified in 4.5% (8/178) of Japanese chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs1800748). -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	-	- -

Tuberous sclerosis 2 Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jul 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 30, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 17, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TSC2: BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 02, 2020	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 25, 2014	This alteration is classified as 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	Oct 23, 2020	- -

Tuberous sclerosis syndrome Benign:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 14, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

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

Jul 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	22
DANN	Benign	0.80
DEOGEN2	Uncertain	0.43	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.038
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0082	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	0.97	D;D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.3	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Benign	0.24
Sift	Benign	0.060	T;.;.;D;.;D;.;.;T;D;.;.;.;.;D
Sift4G	Benign	0.19	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.77	P;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.54
MVP		0.78
ClinPred		0.034	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1800748; hg19: chr16-2108755; COSMIC: COSV54761039; COSMIC: COSV54761039;