rs749593050

chr16-2072880-G-Achr16-2072880-G-Cchr16-2072880-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM5BP4_ModerateBP6

The NM_000548.5(TSC2):c.2252G>A(p.Arg751Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,613,452 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. R751L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 3.86

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 -1 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-2072879-CGA-CT is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.1934292).

BP6

Variant 16-2072880-G-A is Benign according to our data. Variant chr16-2072880-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 535887.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3, Benign=1}. Variant chr16-2072880-G-A is described in Lovd as [Benign]. Variant chr16-2072880-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.2252G>A	p.Arg751Gln	missense_variant	21/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.2252G>A	p.Arg751Gln	missense_variant	21/42	5	NM_000548.5		P49815-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000797

AC:

AN:

250910

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000578

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:

0.00000684

AC:

AN:

1461216

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

726874

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000936

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 10, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 25, 2020	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. Both missense and premature termination codon variants have been shown to affect protein function (ClinVar; PMID 11741832; 18302728) (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from an arginine to a glutamine (exon 21). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (P) 0503 - Missense variant consistently predicted to be tolerated or not conserved in mammals with a minor amino acid change. (B) 0600 - Variant is located in an annotated domain or motif (Tuberin domain). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant is present at a low frequency in the population and has previously been described as variant of uncertain significance in multiple cases (ClinVar; LOVD TSC2 database; PMID 31586081) (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 05, 2023

The p.R751Q variant (also known as c.2252G>A), located in coding exon 20 of the TSC2 gene, results from a G to A substitution at nucleotide position 2252. The arginine at codon 751 is replaced by glutamine, an amino acid with highly similar properties. In one study, this alteration was detected in 1/47 Chinese patients with renal angiomyolipoma associated with tuberous sclerosis complex (Ni J et al. Sci Rep, 2019 10;9:14337). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2021

This variant is associated with the following publications: (PMID: 31586081, 18466115) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Uncertain

0.42

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

Eigen

Benign

-0.088

Eigen_PC

Benign

0.13

FATHMM_MKL

Benign

0.76

LIST_S2

Pathogenic

0.97

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

M_CAP

Benign

0.027

MetaRNN

Benign

0.19

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

MetaSVM

Benign

-0.73

MutationAssessor

Benign

0.0

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

MutationTaster

Benign

0.88

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

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.56

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

REVEL

Uncertain

0.46

Sift

Benign

0.30

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

Sift4G

Benign

0.35

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

Polyphen

0.69

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

Vest4

0.42

MutPred

0.41

Loss of methylation at R751 (P = 0.0386);Loss of methylation at R751 (P = 0.0386);Loss of methylation at R751 (P = 0.0386);.;Loss of methylation at R751 (P = 0.0386);Loss of methylation at R751 (P = 0.0386);Loss of methylation at R751 (P = 0.0386);Loss of methylation at R751 (P = 0.0386);.;Loss of methylation at R751 (P = 0.0386);Loss of methylation at R751 (P = 0.0386);Loss of methylation at R751 (P = 0.0386);Loss of methylation at R751 (P = 0.0386);Loss of methylation at R751 (P = 0.0386);.;

MVP

0.84

ClinPred

0.21

GERP RS

4.6

Varity_R

0.036

gMVP

0.12

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