16-2079415-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000548.5(TSC2):ā€‹c.3271G>Cā€‹(p.Gly1091Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

2
7
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00500
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.281206).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC2NM_000548.5 linkuse as main transcriptc.3271G>C p.Gly1091Arg missense_variant 28/42 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.3271G>C p.Gly1091Arg missense_variant 28/425 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249428
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135466
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459420
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
726046
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 07, 2024The p.G1091R variant (also known as c.3271G>C), located in coding exon 27 of the TSC2 gene, results from a G to C substitution at nucleotide position 3271. The glycine at codon 1091 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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
0.12
BayesDel_addAF
Uncertain
0.034
T
BayesDel_noAF
Benign
-0.090
CADD
Benign
8.4
DANN
Benign
0.97
DEOGEN2
Uncertain
0.74
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
-0.92
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.19
N
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Benign
0.28
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Benign
1.9
M;.;.;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI
Benign
0.41
T
PROVEAN
Uncertain
-2.9
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.010
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Uncertain
0.010
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
0.36
B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4
0.39
MutPred
0.14
Loss of glycosylation at S1090 (P = 0.045);.;Loss of glycosylation at S1090 (P = 0.045);.;.;.;.;Loss of glycosylation at S1090 (P = 0.045);.;Loss of glycosylation at S1090 (P = 0.045);.;.;.;.;.;
MVP
0.91
ClinPred
0.59
D
GERP RS
-3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.090
gMVP
0.39

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.

Other links and lift over

dbSNP: rs796053493; hg19: chr16-2129416; API