chr16-2071884-T-C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_000548.5(TSC2):​c.2047T>C​(p.Ser683Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,596,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. S683Y) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.000013 ( 0 hom., cov: 33)
Exomes š‘“: 0.000017 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

5
14

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: 0.700

Publications

7 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: Benign. The variant received -7 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16846082).
BP6
Variant 16-2071884-T-C is Benign according to our data. Variant chr16-2071884-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 237979.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.2047T>C p.Ser683Pro missense_variant Exon 19 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.2047T>C p.Ser683Pro missense_variant Exon 19 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152176
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000468
AC:
1
AN:
213700
AF XY:
0.00000851
show subpopulations
Gnomad AFR exome
AF:
0.0000810
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:
0.0000166
AC:
24
AN:
1444372
Hom.:
0
Cov.:
33
AF XY:
0.0000181
AC XY:
13
AN XY:
717166
show subpopulations
African (AFR)
AF:
0.0000302
AC:
1
AN:
33106
American (AMR)
AF:
0.00
AC:
0
AN:
42854
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25728
East Asian (EAS)
AF:
0.00
AC:
0
AN:
38844
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83676
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50492
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5670
European-Non Finnish (NFE)
AF:
0.0000181
AC:
20
AN:
1104344
Other (OTH)
AF:
0.0000503
AC:
3
AN:
59658
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.469
Heterozygous variant carriers
0
2
4
6
8
10
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:
0.0000131
AC:
2
AN:
152176
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74340
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41450
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5174
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4834
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10618
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68018
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:4
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:2
Jun 07, 2024
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 serine with proline at codon 683 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 1/213700 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. -

Mar 06, 2024
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This missense variant replaces serine with proline at codon 683 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 1/213700 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. -

Tuberous sclerosis 2 Benign:2
Jan 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Nov 07, 2021
Genome-Nilou Lab
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
May 01, 2023
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

TSC2: BP4 -

Hereditary cancer-predisposing syndrome Benign:1
Sep 14, 2022
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.16
BayesDel_addAF
Uncertain
0.055
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
16
DANN
Benign
0.97
DEOGEN2
Uncertain
0.56
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
-0.99
Eigen_PC
Benign
-0.98
FATHMM_MKL
Benign
0.21
N
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.19
D
MetaRNN
Benign
0.17
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.71
T
MutationAssessor
Benign
-0.14
N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
PhyloP100
0.70
PrimateAI
Benign
0.42
T
PROVEAN
Benign
-1.4
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Uncertain
0.56
Sift
Benign
0.20
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G
Benign
0.064
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen
0.20
B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4
0.44
MutPred
0.61
Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);.;Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);.;Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);.;
MVP
0.86
ClinPred
0.049
T
GERP RS
0.42
Varity_R
0.55
gMVP
0.70
Mutation Taster
=97/3
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: rs878854080; hg19: chr16-2121885; API