16-2084346-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000548.5(TSC2):​c.4124C>T​(p.Ser1375Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

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

Consequence

TSC2
NM_000548.5 missense

Scores

3
11
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 7.24
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.4124C>T p.Ser1375Phe missense_variant Exon 34 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.4124C>T p.Ser1375Phe missense_variant Exon 34 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152236
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:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000402
AC:
1
AN:
248980
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135286
show subpopulations
Gnomad AFR exome
AF:
0.0000623
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152236
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
AN XY:
74360
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:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ESP6500AA
AF:
0.000228
AC:
1
ESP6500EA
AF:
0.00
AC:
0

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Uncertain:1
Feb 08, 2022
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

TSC2-related disorder Uncertain:1
Oct 11, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The TSC2 c.4124C>T variant is predicted to result in the amino acid substitution p.Ser1375Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2134347-C-T). It has conflicting interpretations of benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/577422/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1
Nov 13, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome Uncertain:1
Feb 20, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.S1375F variant (also known as c.4124C>T), located in coding exon 33 of the TSC2 gene, results from a C to T substitution at nucleotide position 4124. The serine at codon 1375 is replaced by phenylalanine, an amino acid with highly 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 alteration remains unclear. -

Tuberous sclerosis 2 Benign:1
Jan 03, 2024
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
0.13
BayesDel_addAF
Pathogenic
0.23
D
BayesDel_noAF
Uncertain
0.10
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.75
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.31
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.96
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.33
D
MetaRNN
Uncertain
0.68
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.14
D
MutationAssessor
Benign
1.9
L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.39
T
PROVEAN
Benign
-2.3
N;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL
Uncertain
0.54
Sift
Uncertain
0.0020
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Uncertain
0.023
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
0.92
P;.;.;.;P;P;.;.;P;P;.;.;.;.;.
Vest4
0.45
MVP
0.87
ClinPred
0.92
D
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.16
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs145476528; hg19: chr16-2134347; API