rs752656474

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000548.5(TSC2):​c.2336A>G​(p.Tyr779Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

TSC2
NM_000548.5 missense

Scores

7
8
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.02
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.839

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC2NM_000548.5 linkuse as main transcriptc.2336A>G p.Tyr779Cys missense_variant 21/42 ENST00000219476.9 NP_000539.2 P49815-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.2336A>G p.Tyr779Cys missense_variant 21/425 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 779 of the TSC2 protein (p.Tyr779Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1510913). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxDec 15, 2022Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 30, 2024The p.Y779C variant (also known as c.2336A>G), located in coding exon 20 of the TSC2 gene, results from an A to G substitution at nucleotide position 2336. The tyrosine at codon 779 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.18
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.46
D
MutationAssessor
Benign
1.4
L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-4.7
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL
Pathogenic
0.76
Sift
Benign
0.033
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Uncertain
0.0090
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
1.0
D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4
0.88
MutPred
0.58
Gain of catalytic residue at L780 (P = 0.0096);Gain of catalytic residue at L780 (P = 0.0096);Gain of catalytic residue at L780 (P = 0.0096);.;Gain of catalytic residue at L780 (P = 0.0096);Gain of catalytic residue at L780 (P = 0.0096);Gain of catalytic residue at L780 (P = 0.0096);Gain of catalytic residue at L780 (P = 0.0096);.;Gain of catalytic residue at L780 (P = 0.0096);Gain of catalytic residue at L780 (P = 0.0096);Gain of catalytic residue at L780 (P = 0.0096);Gain of catalytic residue at L780 (P = 0.0096);Gain of catalytic residue at L780 (P = 0.0096);.;
MVP
0.91
ClinPred
0.98
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.8
Varity_R
0.35
gMVP
0.57

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2122965; API