16-2088218-C-T
Position:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_000548.5(TSC2):c.5161-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,613,134 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Genomes: 𝑓 0.0013 ( 3 hom., cov: 34)
Exomes 𝑓: 0.0014 ( 47 hom. )
Consequence
TSC2
NM_000548.5 splice_polypyrimidine_tract, intron
NM_000548.5 splice_polypyrimidine_tract, intron
Scores
6
Splicing: ADA: 0.00002799
2
Clinical Significance
Conservation
PhyloP100: -0.189
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0026424825).
BP6
Variant 16-2088218-C-T is Benign according to our data. Variant chr16-2088218-C-T is described in ClinVar as [Benign]. Clinvar id is 49854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088218-C-T is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00131 (199/152322) while in subpopulation EAS AF= 0.0349 (181/5184). AF 95% confidence interval is 0.0308. There are 3 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
BS2
High AC in GnomAd4 at 199 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.5161-9C>T | splice_polypyrimidine_tract_variant, intron_variant | ENST00000219476.9 | NP_000539.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.5161-9C>T | splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_000548.5 | ENSP00000219476 |
Frequencies
GnomAD3 genomes AF: 0.00131 AC: 199AN: 152204Hom.: 3 Cov.: 34
GnomAD3 genomes
AF:
AC:
199
AN:
152204
Hom.:
Cov.:
34
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.00322 AC: 807AN: 250712Hom.: 18 AF XY: 0.00287 AC XY: 389AN XY: 135776
GnomAD3 exomes
AF:
AC:
807
AN:
250712
Hom.:
AF XY:
AC XY:
389
AN XY:
135776
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00143 AC: 2083AN: 1460812Hom.: 47 Cov.: 35 AF XY: 0.00137 AC XY: 995AN XY: 726676
GnomAD4 exome
AF:
AC:
2083
AN:
1460812
Hom.:
Cov.:
35
AF XY:
AC XY:
995
AN XY:
726676
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.00131 AC: 199AN: 152322Hom.: 3 Cov.: 34 AF XY: 0.00146 AC XY: 109AN XY: 74484
GnomAD4 genome
AF:
AC:
199
AN:
152322
Hom.:
Cov.:
34
AF XY:
AC XY:
109
AN XY:
74484
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
3
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
2
ExAC
AF:
AC:
419
Asia WGS
AF:
AC:
29
AN:
3478
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Benign
Submissions summary: Benign:15Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:8
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jun 20, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 07, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 21, 2023 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 21, 2013 | 5161-9C>T in intron 40 of TSC2: This variant is not expected to have clinical si gnificance because it has been identified in 4.6% (9/194) of Han Chinese chromos omes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.ni h.gov/projects/SNP; dbSNP rs45515893). - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 06, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Nov 06, 2020 | - - |
Tuberous sclerosis 2 Benign:4
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 21, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 29, 2022 | - - |
Benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Tuberous sclerosis syndrome Benign:1Other:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T
MetaRNN
Benign
T
MutationTaster
Benign
N;N;N;N;N;N;N
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at