rs1440918649

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_000548.5(TSC2):ā€‹c.1121C>Gā€‹(p.Thr374Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense, splice_region

Scores

19
Splicing: ADA: 0.00002981
2

Clinical Significance

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

Conservation

PhyloP100: 0.240
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.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.033101052).
BP6
Variant 16-2061872-C-G is Benign according to our data. Variant chr16-2061872-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 467845.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC2NM_000548.5 linkuse as main transcriptc.1121C>G p.Thr374Ser missense_variant, splice_region_variant 12/42 ENST00000219476.9 NP_000539.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.1121C>G p.Thr374Ser missense_variant, splice_region_variant 12/425 NM_000548.5 ENSP00000219476 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251244
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135886
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:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461812
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727200
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthDec 05, 2022This missense variant replaces threonine with serine at codon 374 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 not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 1/251244 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 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 28, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 467845). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 374 of the TSC2 protein (p.Thr374Ser). -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 12, 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
Benign
0.066
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.46
CADD
Benign
0.44
DANN
Benign
0.56
DEOGEN2
Benign
0.35
T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-0.96
FATHMM_MKL
Benign
0.13
N
LIST_S2
Benign
0.55
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.033
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
MutationTaster
Benign
1.0
N;N;N;N;N;N;N
PrimateAI
Benign
0.32
T
PROVEAN
Benign
-0.52
N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL
Benign
0.049
Sift
Benign
0.50
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G
Benign
0.35
T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen
0.0020
B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4
0.19
MutPred
0.27
Gain of disorder (P = 0.0332);Gain of disorder (P = 0.0332);Gain of disorder (P = 0.0332);.;Gain of disorder (P = 0.0332);Gain of disorder (P = 0.0332);Gain of disorder (P = 0.0332);Gain of disorder (P = 0.0332);.;Gain of disorder (P = 0.0332);Gain of disorder (P = 0.0332);Gain of disorder (P = 0.0332);Gain of disorder (P = 0.0332);Gain of disorder (P = 0.0332);.;
MVP
0.48
ClinPred
0.014
T
GERP RS
1.0
RBP_binding_hub_radar
0.97
RBP_regulation_power_radar
2.1
Varity_R
0.035
gMVP
0.074

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000030
dbscSNV1_RF
Benign
0.020
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1440918649; hg19: chr16-2111873; API