16-2053391-A-T

Position:

chr16-2053391-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000548.5(TSC2):c.275A>T(p.Glu92Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 1,592,736 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00093 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 1 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18O:2

Conservation

PhyloP100: 9.04

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04099989).

BP6

Variant 16-2053391-A-T is Benign according to our data. Variant chr16-2053391-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 50116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2053391-A-T is described in Lovd as [Likely_benign]. Variant chr16-2053391-A-T is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.275A>T	p.Glu92Val	missense_variant	4/42	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.275A>T	p.Glu92Val	missense_variant	4/42	5	NM_000548.5	ENSP00000219476		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.000927

AC:

141

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000848

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00172

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00100

AC:

214

AN:

213250

Hom.:

AF XY:

0.00112

AC XY:

129

AN XY:

115258

show subpopulations

Gnomad AFR exome

AF:

0.0000782

Gnomad AMR exome

AF:

0.000612

Gnomad ASJ exome

AF:

0.000431

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000377

Gnomad FIN exome

AF:

0.00112

Gnomad NFE exome

AF:

0.00164

Gnomad OTH exome

AF:

0.000932

GnomAD4 exome

AF:

0.00129

AC:

1862

AN:

1440434

Hom.:

Cov.:

AF XY:

0.00129

AC XY:

921

AN XY:

714558

show subpopulations

Gnomad4 AFR exome

AF:

0.000151

Gnomad4 AMR exome

AF:

0.000860

Gnomad4 ASJ exome

AF:

0.000428

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000339

Gnomad4 FIN exome

AF:

0.00149

Gnomad4 NFE exome

AF:

0.00148

Gnomad4 OTH exome

AF:

0.00114

GnomAD4 genome

AF:

0.000926

AC:

141

AN:

152302

Hom.:

Cov.:

AF XY:

0.000926

AC XY:

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000523

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000848

Gnomad4 NFE

AF:

0.00172

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00127

Hom.:

Bravo

AF:

0.000763

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00221

AC:

ExAC

AF:

0.000833

AC:

100

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
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	Aug 10, 2022	- -

not provided

Benign:5

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	TSC2: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 19, 2019	This variant is associated with the following publications: (PMID: 21407264, 23514105, 22558107, 21624971, 24728327, 28873162, 29801666) -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 14, 2019	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:4Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 01, 2020	The c.275A>T variant in TSC2 has been reported in individuals with Tuberous Sclerosis Complex (Dunlop 2011 PMID: 21407264, Bullich 2018 PMID: 29801666); however, it has also been identified in 0.17% (189/109664) of Finnish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 50116). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant is classified as Likely Benign due to its frequency in the general population. ACMG/AMP Criteria applied: BS1, BP4. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 27, 2020	Variant summary: TSC2 c.275A>T (p.Glu92Val) results in a non-conservative amino acid change located in the N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 213250 control chromosomes (gnomAD). The observed variant frequency is approximately 14.6- fold the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. c.275A>T has been reported in the literature in individuals affected with Tuberous Sclerosis Complex (examples-Dunlop_2011, Bullich_2018) and in at least one unaffected family member (Dunlop_2011). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Dunlop_2011). Seven ClinVar submitters (evaluation after 2014) classified the variant as benign (n=2)/likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 18, 2018	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	Sep 21, 2020	- -

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 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.83

D;.;.;.;.;.;.;.;.;.;.;.;T;.;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

D;D;D;D;D;D;D;D;D;T;D;D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Benign

0.041

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.10

MutationAssessor

Uncertain

2.1

M;.;.;.;M;M;.;.;M;.;.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-4.0

D;.;.;D;.;D;.;.;D;.;.;.;.;.;D

REVEL

Uncertain

0.56

Sift

Uncertain

0.0020

D;.;.;D;.;D;.;.;D;.;.;.;.;.;D

Sift4G

Uncertain

0.0030

D;.;.;D;.;D;.;.;D;.;.;.;.;.;D

Polyphen

1.0

D;.;.;.;.;B;.;.;B;.;.;.;.;.;.

Vest4

0.63

MVP

0.76

ClinPred

0.12

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.41

gMVP

0.58

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

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