16-2079289-G-A

Position:

chr16-2079289-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PM1PP3_StrongBP6BS2

The NM_000548.5(TSC2):c.3145G>A(p.Glu1049Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1049Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:2

Conservation

PhyloP100: 9.57

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 Uncertain_significance. Variant got 1 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 13 uncertain in NM_000548.5

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

BP6

Variant 16-2079289-G-A is Benign according to our data. Variant chr16-2079289-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207741.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}. Variant chr16-2079289-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.3145G>A	p.Glu1049Lys	missense_variant	28/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.3145G>A	p.Glu1049Lys	missense_variant	28/42	5	NM_000548.5		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1460704

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

726644

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 11, 2017	The E1049K variant in the TSC2 gene was reported previously in a fetus with cardiac rhabdomyoma noted on ultrasound and confirmed at birth (Milunsky et al., 2009). However, no other features of TSC were noted in the patient, it is unknown whether there was a family history of TSC, and the parents were not tested for the variant. The E1049K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations.The E1049K variant is a non-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret E1049K as a variant of unknown significance. -
Uncertain significance, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Tuberous sclerosis 2

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Absent from ExAC. Detected in control and affected groups in autism study. Also published in study of pregnant women at risk for having child with TSC. No other pubs found. -

Tuberous sclerosis syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Nov 20, 2023

This missense variant replaces glutamic acid with lysine at codon 1049 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an infant with a diagnosis of cardiac rhabdomyoma via fetal ultrasound and confirmed at birth that underwent prenatal genetic testing for tuberous sclerosis complex (PMID: 19254590). The infant had no other features of tuberous sclerosis complex and there was no known family history. This variant has been identified in 1/31354 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

TSC2-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 18, 2023

The TSC2 c.3145G>A variant is predicted to result in the amino acid substitution p.Glu1049Lys. This variant was reported in an individual with tuberous sclerosis (Milunsky et al 2009. PubMed ID: 19254590). This variant is reported in 0.0065% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2129290-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Isolated focal cortical dysplasia type II

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 15, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2022

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.43

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.83

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

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.38

MetaRNN

Pathogenic

0.96

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

MetaSVM

Pathogenic

0.86

MutationAssessor

Uncertain

2.6

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.86

PROVEAN

Uncertain

-3.3

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

REVEL

Pathogenic

0.93

Sift

Benign

0.030

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

Sift4G

Uncertain

0.011

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

Polyphen

1.0

D;.;.;.;D;D;.;.;P;D;.;.;.;.;.

Vest4

0.84

MutPred

0.86

Gain of MoRF binding (P = 0.0025);.;Gain of MoRF binding (P = 0.0025);.;.;.;.;Gain of MoRF binding (P = 0.0025);.;Gain of MoRF binding (P = 0.0025);.;.;.;.;.;

MVP

0.99

ClinPred

0.99

GERP RS

4.7

Varity_R

0.55

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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