16-2079637-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM2PM5BP4BS2

The NM_000548.5(TSC2):​c.3365G>C​(p.Arg1122Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,848 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. R1122C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

2
9
8

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 3.55
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-2079636-C-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.3963635).
BS2
High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.3365G>C p.Arg1122Pro missense_variant Exon 29 of 42 ENST00000219476.9 NP_000539.2 P49815-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkc.3365G>C p.Arg1122Pro missense_variant Exon 29 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000344
AC:
5
AN:
1454848
Hom.:
0
Cov.:
32
AF XY:
0.00000553
AC XY:
4
AN XY:
723222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1Benign:1
May 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 07, 2021
Genome-Nilou Lab
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1
Jul 09, 2018
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

A variant of uncertain significance has been identified in the TSC2 gene. The R1122P variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The R1122P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R1122P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved. Additionally, this substitution does not occur within known functional domains of the tuberin protein, where many pathogenic missense variants have been identified (Northrup et al., 2011; Au et al., 2007). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Hereditary cancer-predisposing syndrome Uncertain:1
Apr 13, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R1122P variant (also known as c.3365G>C), located in coding exon 28 of the TSC2 gene, results from a G to C substitution at nucleotide position 3365. The arginine at codon 1122 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Pathogenic
0.29
D
BayesDel_noAF
Pathogenic
0.18
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.56
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
0.094
Eigen_PC
Benign
0.080
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.077
D
MetaRNN
Benign
0.40
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.045
D
MutationAssessor
Uncertain
2.1
M;.;.;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-1.9
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
0.57
Sift
Uncertain
0.012
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Uncertain
0.059
T;.;.;D;.;D;.;.;D;T;.;.;.;.;D
Polyphen
0.92
P;.;.;.;P;P;.;.;P;P;.;.;.;.;.
Vest4
0.64
MutPred
0.22
Loss of MoRF binding (P = 0.0066);.;Loss of MoRF binding (P = 0.0066);.;.;.;.;Loss of MoRF binding (P = 0.0066);.;Loss of MoRF binding (P = 0.0066);.;.;.;.;.;
MVP
0.98
ClinPred
0.79
D
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.2
Varity_R
0.23
gMVP
0.45

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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.

Other links and lift over

dbSNP: rs369536711; hg19: chr16-2129638; API