rs757221445

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 6P and 5B. PM1PP3_StrongBP6BS2

The NM_000548.5(TSC2):​c.4998C>A​(p.Phe1666Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,612,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

12
6
1

Clinical Significance

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

Conservation

PhyloP100: 2.28
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 1 ACMG points.

PM1
In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 284 pathogenic changes around while only 47 benign (86%) in NM_000548.5
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
BP6
Variant 16-2087871-C-A is Benign according to our data. Variant chr16-2087871-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 207690.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}.
BS2
High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
TSC2NM_000548.5 linkuse as main transcriptc.4998C>A p.Phe1666Leu missense_variant 39/42 ENST00000219476.9 NP_000539.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.4998C>A p.Phe1666Leu missense_variant 39/425 NM_000548.5 ENSP00000219476 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152076
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000288
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000801
AC:
2
AN:
249546
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135530
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000200
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
AF:
0.00000411
AC:
6
AN:
1460228
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
726392
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000191
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
AF:
0.00000658
AC:
1
AN:
152076
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000282
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000826
AC:
1

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Jan 12, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 02, 2022The p.F1666L variant (also known as c.4998C>A), located in coding exon 38 of the TSC2 gene, results from a C to A substitution at nucleotide position 4998. The phenylalanine at codon 1666 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Tuberous sclerosis 2 Benign:2
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 28, 2024- -
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Tuberous sclerosis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthAug 15, 2023This missense variant replaces phenylalanine with leucine at codon 1666 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 TSC2-related disorders in the literature. This variant has been identified in 3/280940 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
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 05, 2020In 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 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.49
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.95
D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen
Uncertain
0.64
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.94
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.0
D
MutationAssessor
Pathogenic
3.3
M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.89
D
PROVEAN
Pathogenic
-5.1
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL
Pathogenic
0.91
Sift
Uncertain
0.0060
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Pathogenic
0.0
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
0.99
D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4
0.88
MutPred
0.93
Loss of sheet (P = 0.1158);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.98
ClinPred
0.98
D
GERP RS
4.6
Varity_R
0.84
gMVP
0.85

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs757221445; hg19: chr16-2137872; COSMIC: COSV51922542; COSMIC: COSV51922542; API