rs759790981

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000548.5(TSC2):​c.3964G>A​(p.Ala1322Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,611,098 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.538
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.10516143).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC2NM_000548.5 linkuse as main transcriptc.3964G>A p.Ala1322Thr missense_variant 33/42 ENST00000219476.9 NP_000539.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.3964G>A p.Ala1322Thr missense_variant 33/425 NM_000548.5 ENSP00000219476 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1458894
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
725526
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0

ClinVar

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

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 03, 2022In 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. 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. ClinVar contains an entry for this variant (Variation ID: 568497). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1322 of the TSC2 protein (p.Ala1322Thr). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Uncertain
0.080
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
11
DANN
Benign
0.93
DEOGEN2
Benign
0.41
T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
-0.94
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.75
D
LIST_S2
Benign
0.84
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.11
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.43
T
MutationAssessor
Benign
1.1
L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
0.90
D;D;D;D;D;D;D
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-0.76
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
0.51
Sift
Benign
0.55
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G
Benign
0.60
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen
0.0
B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4
0.097
MutPred
0.22
Loss of helix (P = 0.0376);.;.;.;.;.;.;Loss of helix (P = 0.0376);.;.;.;.;.;.;.;
MVP
0.90
ClinPred
0.092
T
GERP RS
3.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.031
gMVP
0.32

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: rs759790981; hg19: chr16-2133776; API