rs747237113

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM1PP3_ModerateBS2

The NM_000548.5(TSC2):​c.886G>A​(p.Val296Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000377 in 1,593,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V296L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

14
4
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3B:1

Conservation

PhyloP100: 9.51

Publications

6 publications found
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 Gene-Disease associations (from GenCC):
  • tuberous sclerosis
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • tuberous sclerosis 2
    Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
  • lymphangioleiomyomatosis
    Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
  • tuberous sclerosis complex
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_000548.5
PP3
MetaRNN computational evidence supports a deleterious effect, 0.867
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.886G>A p.Val296Met missense_variant Exon 10 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.886G>A p.Val296Met missense_variant Exon 10 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152236
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000464
AC:
1
AN:
215604
AF XY:
0.00
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000331
Gnomad ASJ exome
AF:
0.00
Gnomad EAS 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:
0.00000347
AC:
5
AN:
1441318
Hom.:
0
Cov.:
32
AF XY:
0.00000280
AC XY:
2
AN XY:
714914
show subpopulations
African (AFR)
AF:
0.0000600
AC:
2
AN:
33358
American (AMR)
AF:
0.0000244
AC:
1
AN:
41014
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25606
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39218
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83034
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51940
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5672
European-Non Finnish (NFE)
AF:
0.00000182
AC:
2
AN:
1101840
Other (OTH)
AF:
0.00
AC:
0
AN:
59636
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152236
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74382
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41464
American (AMR)
AF:
0.00
AC:
0
AN:
15290
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68036
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.625
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1Benign:1
Dec 15, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely 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

- -

Lymphangiomyomatosis Pathogenic:1
Jan 01, 2016
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was classified as: Likely pathogenic. -

Cortical tubers Pathogenic:1
Sep 19, 2014
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Sep 23, 2022
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Observed in a patient with epilepsy, learning disability, facial angiofibromas, and renal cysts; paternally inherited, although no clinical information was provided for the father (Tumiene et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 18466115, 29286531) -

Hereditary cancer-predisposing syndrome Uncertain:1
Jul 25, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.V296M variant (also known as c.886G>A), located in coding exon 9 of the TSC2 gene, results from a G to A substitution at nucleotide position 886. The valine at codon 296 is replaced by methionine, an amino acid with highly similar properties. This alteration was detected in an individual with a personal history of epilepsy, specific learning disability, facial angiofibromas and renal cysts (Tumien B et al. Clin Genet, 2018 05;93:1057-1062). This amino acid position is highly 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
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.45
D
BayesDel_noAF
Pathogenic
0.41
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.81
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.83
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.61
D
MetaRNN
Pathogenic
0.87
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Uncertain
2.4
M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PhyloP100
9.5
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-2.5
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0020
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Pathogenic
0.0
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
1.0
D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4
0.92
MVP
0.98
ClinPred
0.93
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.63
gMVP
0.72
Mutation Taster
=0/100
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs747237113; hg19: chr16-2108785; API