rs774506901

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000548.5(TSC2):​c.199G>A​(p.Val67Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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. V67F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

5
14

Clinical Significance

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

Conservation

PhyloP100: 3.56

Publications

4 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: Likely_benign. The variant received -1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12956595).
BP6
Variant 16-2050460-G-A is Benign according to our data. Variant chr16-2050460-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 535927.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.199G>A p.Val67Ile missense_variant Exon 3 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.199G>A p.Val67Ile missense_variant Exon 3 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251106
AF XY:
0.0000147
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461732
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727152
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44718
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.0000232
AC:
2
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53344
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111946
Other (OTH)
AF:
0.00
AC:
0
AN:
60390
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
30
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1
Oct 02, 2023
All of Us Research Program, National Institutes of Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces valine with isoleucine at codon 67 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with autism spectrum disorder in the literature (PMID: 30763456). This variant has been identified in 2/251106 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Uncertain:1
Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TSC2: PM2, BP4 -

Hereditary cancer-predisposing syndrome Uncertain:1
Sep 23, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.V67I variant (also known as c.199G>A), located in coding exon 2 of the TSC2 gene, results from a G to A substitution at nucleotide position 199. The valine at codon 67 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Tuberous sclerosis 2 Benign:1
Jul 07, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.090
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.21
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.34
T;.;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.22
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Uncertain
0.88
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Benign
0.064
D
MetaRNN
Benign
0.13
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.25
T
MutationAssessor
Benign
1.2
L;.;.;.;L;L;.;.;L;L;.;.;L;.;.;.
PhyloP100
3.6
PrimateAI
Uncertain
0.50
T
PROVEAN
Benign
-0.25
N;.;.;N;.;N;.;.;N;N;.;.;.;.;.;N
REVEL
Benign
0.17
Sift
Benign
0.15
T;.;.;T;.;T;.;.;T;T;.;.;.;.;.;T
Sift4G
Benign
0.31
T;.;.;T;.;T;.;.;T;T;.;.;.;.;.;T
Polyphen
0.97
D;.;.;.;.;B;.;.;B;B;.;.;.;.;.;.
Vest4
0.28
MutPred
0.35
Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);.;Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);Loss of MoRF binding (P = 0.1108);.;
MVP
0.53
ClinPred
0.21
T
GERP RS
2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.024
gMVP
0.12
Mutation Taster
=91/9
polymorphism

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

Other links and lift over

dbSNP: rs774506901; hg19: chr16-2100461; API