16-2053391-A-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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:19O: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 -20 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].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000926 (141/152302) while in subpopulation NFE AF= 0.00172 (117/68028). AF 95% confidence interval is 0.00147. There are 0 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 141 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.275A>T	p.Glu92Val	missense_variant	Exon 4 of 42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.275A>T	p.Glu92Val	missense_variant	Exon 4 of 42	5	NM_000548.5	ENSP00000219476.3		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:19Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Benign:5

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:5

Mar 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21407264, 23514105, 22558107, 21624971, 24728327, 28873162, 29801666) -

Nov 07, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 14, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TSC2: BP4, BS1, BS2 -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:4Other:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Jul 01, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 27, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2020

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Tuberous sclerosis syndrome

Benign:2Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Aug 10, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome

Benign:2

Dec 18, 2018

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 21, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

Benign:1

Apr 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.;.

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