chr16-2055399-C-T

Variant names:

• chr16-2055399-C-T
• rs1800720
• NM_000548.5:c.482-3C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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: Splicing: ADA: 0.0006049
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:17 O:3
• Conservation: PhyloP100: 0.111

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]

ACMG classification

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
TSC2	NM_000548.5	c.482-3C>T		splice_region_variant, intron_variant	Intron 5 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.482-3C>T		splice_region_variant, intron_variant	Intron 5 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.123 AC: 18710 AN: 152068 Hom.: 1375 Cov.: 32

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

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

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

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:17 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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). -

-

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. -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Tuberous sclerosis 2 Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Nov 07, 2021

Genome-Nilou Lab

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

- -

Apr 14, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Benign:1 Other: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

Other links and lift over

dbSNP: rs1800720; hg19: chr16-2105400; COSMIC: COSV54755039; COSMIC: COSV54755039;