rs397515223

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4BP6BS2

The NM_000548.5(TSC2):c.1973A>C(p.Lys658Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,604,130 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7O:2

Conservation

PhyloP100: 6.92

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2722392).

BP6

Variant 16-2071810-A-C is Benign according to our data. Variant chr16-2071810-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 65307.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5, not_provided=2, Benign=2}. Variant chr16-2071810-A-C is described in Lovd as [Likely_benign]. Variant chr16-2071810-A-C is described in Lovd as [Benign].

BS2

High AC in GnomAd4 at 33 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.1973A>C	p.Lys658Thr	missense_variant	19/42	ENST00000219476.9	NP_000539.2	P49815-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.1973A>C	p.Lys658Thr	missense_variant	19/42	5	NM_000548.5	ENSP00000219476.3		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.000218

AC:

AN:

151696

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000389

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00142

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000280

AC:

AN:

228820

Hom.:

AF XY:

0.000271

AC XY:

AN XY:

125332

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000300

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000173

Gnomad SAS exome

AF:

0.000315

Gnomad FIN exome

AF:

0.00133

Gnomad NFE exome

AF:

0.000128

Gnomad OTH exome

AF:

0.000534

GnomAD4 exome

AF:

0.000191

AC:

277

AN:

1452320

Hom.:

Cov.:

AF XY:

0.000204

AC XY:

147

AN XY:

721654

show subpopulations

Gnomad4 AFR exome

AF:

0.0000600

Gnomad4 AMR exome

AF:

0.000251

Gnomad4 ASJ exome

AF:

0.0000387

Gnomad4 EAS exome

AF:

0.000229

Gnomad4 SAS exome

AF:

0.000260

Gnomad4 FIN exome

AF:

0.00173

Gnomad4 NFE exome

AF:

0.000116

Gnomad4 OTH exome

AF:

0.000217

GnomAD4 genome

AF:

0.000217

AC:

AN:

151810

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000390

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00142

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000336

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000199

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7Other:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2021	This variant is associated with the following publications: (PMID: 24728327, 22903760, 23514105, 21309039) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	TSC2: BS3:Supporting, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Tuberous sclerosis syndrome

Uncertain:1Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Tuberous sclerosis 2

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2019	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. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.59

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

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

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

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.27

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

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

1.7

L;.;.;.;L;L;.;.;.;L;.;L;.;.;.

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-2.1

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

REVEL

Pathogenic

0.71

Sift

Uncertain

0.014

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

Sift4G

Uncertain

0.0060

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

Polyphen

1.0

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

Vest4

0.52

MVP

0.81

ClinPred

0.093

GERP RS

5.5

Varity_R

0.23

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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