16-2055399-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000548.5(TSC2):​c.482-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0951 in 1,613,492 control chromosomes in the GnomAD database, including 8,382 homozygotes. In-silico tool predicts 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 Benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1381 hom., cov: 32)
Exomes 𝑓: 0.092 ( 7001 hom. )

Consequence

TSC2
NM_000548.5 splice_region, intron

Scores

2
Splicing: ADA: 0.0006049
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O:3

Conservation

PhyloP100: 0.111
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 Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 16-2055399-C-T is Benign according to our data. Variant chr16-2055399-C-T is described in ClinVar as [Benign]. Clinvar id is 49957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2055399-C-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.194 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.482-3C>T splice_region_variant, intron_variant Intron 5 of 41 ENST00000219476.9 NP_000539.2 P49815-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkc.482-3C>T splice_region_variant, intron_variant Intron 5 of 41 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
AF:
0.123
AC:
18710
AN:
152068
Hom.:
1375
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.197
Gnomad AMI
AF:
0.0833
Gnomad AMR
AF:
0.0949
Gnomad ASJ
AF:
0.146
Gnomad EAS
AF:
0.000770
Gnomad SAS
AF:
0.0280
Gnomad FIN
AF:
0.135
Gnomad MID
AF:
0.146
Gnomad NFE
AF:
0.0974
Gnomad OTH
AF:
0.127
GnomAD3 exomes
AF:
0.0868
AC:
21836
AN:
251444
Hom.:
1315
AF XY:
0.0840
AC XY:
11413
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.200
Gnomad AMR exome
AF:
0.0571
Gnomad ASJ exome
AF:
0.138
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0259
Gnomad FIN exome
AF:
0.129
Gnomad NFE exome
AF:
0.0966
Gnomad OTH exome
AF:
0.105
GnomAD4 exome
AF:
0.0922
AC:
134667
AN:
1461306
Hom.:
7001
Cov.:
31
AF XY:
0.0898
AC XY:
65260
AN XY:
727010
show subpopulations
Gnomad4 AFR exome
AF:
0.203
Gnomad4 AMR exome
AF:
0.0622
Gnomad4 ASJ exome
AF:
0.140
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.0291
Gnomad4 FIN exome
AF:
0.126
Gnomad4 NFE exome
AF:
0.0950
Gnomad4 OTH exome
AF:
0.0962
GnomAD4 genome
AF:
0.123
AC:
18740
AN:
152186
Hom.:
1381
Cov.:
32
AF XY:
0.122
AC XY:
9081
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.198
Gnomad4 AMR
AF:
0.0947
Gnomad4 ASJ
AF:
0.146
Gnomad4 EAS
AF:
0.000772
Gnomad4 SAS
AF:
0.0278
Gnomad4 FIN
AF:
0.135
Gnomad4 NFE
AF:
0.0974
Gnomad4 OTH
AF:
0.125
Alfa
AF:
0.111
Hom.:
1447
Bravo
AF:
0.125
Asia WGS
AF:
0.0250
AC:
88
AN:
3478
EpiCase
AF:
0.106
EpiControl
AF:
0.107

ClinVar

Significance: Benign
Submissions summary: Benign:17Other:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Feb 21, 2013
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

482-3C>T in intron 5 of TSC2: This variant is not expected to have clinical sign ificance because it has been identified in 19.1% (838/4396) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs1800720). -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genetic Services Laboratory, University of Chicago
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tuberous sclerosis 2 Benign:5
Apr 14, 2017
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 05, 2018
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 07, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:4
Nov 25, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 23, 2016
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: c.482-3C>T in TSC2 gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.087 (10574/121392 chrs tested), predominantly in individuals of African descent (0.2; 2098/10406 chrs tested) including numerous homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.00006 suggesting that it is a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but cited as Benign/ Likely Benign by multiple reputable databases/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Benign:1Other:1
-
Tuberous sclerosis database (TSC2)
Significance: not provided
Review Status: no classification provided
Collection Method: curation

- -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Benign:1
Nov 21, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Tuberous sclerosis syndrome;C0751674:Lymphangiomyomatosis Other:1
-
Tuberous sclerosis database (TSC2)
Significance: not provided
Review Status: no classification provided
Collection Method: curation

- -

Neoplasm of brain Other:1
-
Tuberous sclerosis database (TSC2)
Significance: not provided
Review Status: no classification provided
Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.81
CADD
Benign
6.6
DANN
Benign
0.32
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.9

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00060
dbscSNV1_RF
Benign
0.074
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: rs1800720; hg19: chr16-2105400; COSMIC: COSV54755039; COSMIC: COSV54755039; API