rs13331451

chr16-2075787-C-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.2546-12C>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 0.0917 in 1,611,716 control chromosomes in the GnomAD database, including 15,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (6593 hom., cov: 32)
  • Exomes 𝑓: 0.080 (9103 hom.)
• Consequence: TSC2 NM_000548.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001352
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13 O:1
• Conservation: PhyloP100: -0.551

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=-0.9).
• BP6: Variant 16-2075787-C-T is Benign according to our data. Variant chr16-2075787-C-T is described in ClinVar as [Benign]. Clinvar id is 49214.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2075787-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.537 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.2546-12C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2546-12C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30916 AN: 152016 Hom.: 6566 Cov.: 32

Gnomad AFR AF: 0.542

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0712

Gnomad EAS AF: 0.000773

Gnomad SAS AF: 0.0487

Gnomad FIN AF: 0.0993

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0685

Gnomad OTH AF: 0.171

GnomAD3 exomes AF: 0.0953 AC: 23714 AN: 248848 Hom.: 3005 AF XY: 0.0863 AC XY: 11678 AN XY: 135286

Gnomad AFR exome AF: 0.549

Gnomad AMR exome AF: 0.0637

Gnomad ASJ exome AF: 0.0734

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.0478

Gnomad FIN exome AF: 0.0974

Gnomad NFE exome AF: 0.0712

Gnomad OTH exome AF: 0.0792

GnomAD4 exome AF: 0.0801 AC: 116840 AN: 1459582 Hom.: 9103 Cov.: 33 AF XY: 0.0774 AC XY: 56226 AN XY: 726164

Gnomad4 AFR exome AF: 0.560

Gnomad4 AMR exome AF: 0.0692

Gnomad4 ASJ exome AF: 0.0754

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0483

Gnomad4 FIN exome AF: 0.0979

Gnomad4 NFE exome AF: 0.0696

Gnomad4 OTH exome AF: 0.0978

GnomAD4 genome AF: 0.204 AC: 30995 AN: 152134 Hom.: 6593 Cov.: 32 AF XY: 0.201 AC XY: 14967 AN XY: 74376

Gnomad4 AFR AF: 0.542

Gnomad4 AMR AF: 0.122

Gnomad4 ASJ AF: 0.0712

Gnomad4 EAS AF: 0.000775

Gnomad4 SAS AF: 0.0484

Gnomad4 FIN AF: 0.0993

Gnomad4 NFE AF: 0.0685

Gnomad4 OTH AF: 0.169

Alfa AF: 0.0888 Hom.: 1260

Bravo AF: 0.218

Asia WGS AF: 0.0680 AC: 237 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:13 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2014	- -
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	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2013	2546-12C>T in intron 22 of TSC2: This variant is not expected to have clinical s ignificance because it has been identified in 47.9% (2106/4396) of African Ameri can chromosomes from a broad population by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS; dbSNP rs13331451). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Tuberous sclerosis 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 28, 2019	- -

Tuberous sclerosis syndrome Benign:2 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.32
Dann	Benign	0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
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: rs13331451; hg19: chr16-2125788; COSMIC: COSV54756570; COSMIC: COSV54756570;