chr16-2087890-G-C

Position:

chr16-2087890-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBS1BS2

The NM_000548.5(TSC2):c.5017G>C(p.Val1673Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000221 in 1,612,026 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts 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. V1673D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00023 ( 6 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7O:2

Conservation

PhyloP100: 6.23

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.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 9 benign, 14 uncertain in NM_000548.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-2087891-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 448735.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.0126879215).

BP6

Variant 16-2087890-G-C is Benign according to our data. Variant chr16-2087890-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 49495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2087890-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000234 (342/1460060) while in subpopulation SAS AF= 0.00384 (331/86244). AF 95% confidence interval is 0.0035. There are 6 homozygotes in gnomad4_exome. There are 222 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.5017G>C	p.Val1673Leu	missense_variant	39/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.5017G>C	p.Val1673Leu	missense_variant	39/42	5	NM_000548.5		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.0000988

AC:

AN:

151850

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:

0.00311

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000500

AC:

125

AN:

249792

Hom.:

AF XY:

0.000634

AC XY:

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00399

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.000234

AC:

342

AN:

1460060

Hom.:

Cov.:

AF XY:

0.000306

AC XY:

222

AN XY:

726318

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00384

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000987

AC:

AN:

151966

Hom.:

Cov.:

AF XY:

0.000162

AC XY:

AN XY:

74298

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:

0.00311

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000264

ExAC

AF:

0.000677

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 11, 2022	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2021	This variant is associated with the following publications: (PMID: 24728327, 15595939, 28991257) -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 08, 2016	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. -

TSC2-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 15, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Tuberous sclerosis syndrome

Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.79

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

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.089

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

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

M_CAP

Pathogenic

0.56

MetaRNN

Benign

0.013

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

MetaSVM

Uncertain

0.49

MutationAssessor

Uncertain

2.4

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

MutationTaster

Benign

0.98

N;N;N;N;N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.5

N;.;.;N;.;N;.;.;N;N;.;.;.;.;N

REVEL

Uncertain

0.60

Sift

Uncertain

0.0060

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

Sift4G

Uncertain

0.013

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

Polyphen

0.043

B;.;.;.;B;B;.;.;B;B;.;.;.;.;.

Vest4

0.56

MutPred

0.43

Loss of sheet (P = 0.3635);.;.;.;.;.;.;.;.;.;.;.;.;.;.;

MVP

0.71

ClinPred

0.096

GERP RS

3.5

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.6

Varity_R

0.64

gMVP

0.48

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