16-2079667-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP6BS2

The NM_000548.5(TSC2):​c.3395C>T​(p.Ser1132Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000146 in 1,435,474 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1132S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense, splice_region

Scores

8
10
1
Splicing: ADA: 0.9995
2

Clinical Significance

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

Conservation

PhyloP100: 7.22
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a modified_residue Phosphoserine (size 0) in uniprot entity TSC2_HUMAN
BP6
Variant 16-2079667-C-T is Benign according to our data. Variant chr16-2079667-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406107.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}.
BS2
High AC in GnomAdExome4 at 21 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.3395C>T p.Ser1132Leu missense_variant, splice_region_variant Exon 29 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.3395C>T p.Ser1132Leu missense_variant, splice_region_variant Exon 29 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000988
AC:
2
AN:
202498
Hom.:
0
AF XY:
0.0000183
AC XY:
2
AN XY:
109536
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000114
Gnomad OTH exome
AF:
0.000194
GnomAD4 exome
AF:
0.0000146
AC:
21
AN:
1435474
Hom.:
0
Cov.:
31
AF XY:
0.0000126
AC XY:
9
AN XY:
711850
show subpopulations
Gnomad4 AFR exome
AF:
0.0000605
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:
0.0000136
Gnomad4 OTH exome
AF:
0.0000338
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000283
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.00000841
AC:
1

ClinVar

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

Submissions by phenotype

not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxJul 31, 2023In 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 -
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoDec 05, 2023- -
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenNov 01, 2024TSC2: BS2 -
Tuberous sclerosis 2 Benign:2
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2025- -
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 03, 2022This 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
Pathogenic
0.65
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.81
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.63
D
MetaRNN
Uncertain
0.70
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.89
D
MutationAssessor
Uncertain
2.3
M;.;.;.;.;.;.;.;.;M;.;.;.;.;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Uncertain
-3.5
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0080
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Uncertain
0.0030
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
1.0
D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4
0.86
MutPred
0.25
Loss of relative solvent accessibility (P = 0.0071);.;Loss of relative solvent accessibility (P = 0.0071);.;.;.;.;Loss of relative solvent accessibility (P = 0.0071);.;Loss of relative solvent accessibility (P = 0.0071);.;.;.;.;.;
MVP
0.91
ClinPred
0.92
D
GERP RS
4.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.8
Varity_R
0.23
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.86
SpliceAI score (max)
0.11
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: rs137854074; hg19: chr16-2129668; COSMIC: COSV54772356; COSMIC: COSV54772356; API