rs45517202

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2PM5BP4BP6

The NM_000548.5(TSC2):c.1796A>G(p.Lys599Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. K599M) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.95

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-2070535-A-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.31025937).

BP6

Variant 16-2070535-A-G is Benign according to our data. Variant chr16-2070535-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207722.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.1796A>G	p.Lys599Arg	missense_variant	17/42	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.1796A>G	p.Lys599Arg	missense_variant	17/42	5	NM_000548.5	ENSP00000219476		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250664

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.0000618

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460946

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726784

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 31, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 28, 2012

p.Lys599Arg (AAG>AGG):c.1796 A>G in exon 17 of the TSC2 gene (NM_000548.3)The Lys599Arg missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. A different amino acid substitution at the same position, Lys599Met, was previously reported as a de novo mutation in a patient with sporadic tuberous sclerosis, and some in vitro studies suggested it may alter protein function; however, subsequent studies revealed no effect on protein function, and at this time the clinical significance of Lys599Met is unknown (Niida et al., 1999; Tee et al., 2002; Nellist et al., 2005; Hoogeveen-Westerveld et al., 2011; LOVD; an external gene datebase). The NHLBI ESP Exome Variant Project has not identified Lys599Arg in approximately 6,500 individuals of European or African American ethnicity, indicating that it is not a common benign variant in these populations. The amino acid substitution is conservative, as both Lysine and Arginine are positively charged amino acids. Lys599Arg alters a position in the tuberin protein that is not conserved. While one in silico algorithm predicts it may be damaging to protein structure/function, another model predicts it is likely benign. Therefore, based on the currently available information, it is unclear whether Lys599Arg is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

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

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.20

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.85

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

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.31

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

MetaSVM

Benign

-0.36

MutationAssessor

Benign

1.9

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

MutationTaster

Benign

0.99

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

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.3

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

REVEL

Uncertain

0.56

Sift

Benign

0.13

T;.;.;T;.;T;.;.;T;T;.;.;.;.;T

Sift4G

Uncertain

0.041

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

Polyphen

0.85

P;.;.;.;B;B;.;.;B;B;.;.;.;.;.

Vest4

0.42

MutPred

0.52

Loss of ubiquitination at K599 (P = 0.0199);Loss of ubiquitination at K599 (P = 0.0199);Loss of ubiquitination at K599 (P = 0.0199);.;Loss of ubiquitination at K599 (P = 0.0199);Loss of ubiquitination at K599 (P = 0.0199);Loss of ubiquitination at K599 (P = 0.0199);Loss of ubiquitination at K599 (P = 0.0199);.;Loss of ubiquitination at K599 (P = 0.0199);Loss of ubiquitination at K599 (P = 0.0199);Loss of ubiquitination at K599 (P = 0.0199);Loss of ubiquitination at K599 (P = 0.0199);Loss of ubiquitination at K599 (P = 0.0199);.;

MVP

0.71

ClinPred

0.078

GERP RS

2.1

Varity_R

0.046

gMVP

0.31

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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