16-2088421-C-G

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.5260-25C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 1,612,392 control chromosomes in the GnomAD database, including 17,989 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (5899 hom., cov: 33)
  • Exomes 𝑓: 0.11 (12090 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.527

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=-0.8).
• BP6: Variant 16-2088421-C-G is Benign according to our data. Variant chr16-2088421-C-G is described in ClinVar as [Benign]. Clinvar id is 49976.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2088421-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.489 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.5260-25C>G		intron_variant		ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.5260-25C>G		intron_variant		5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32400 AN: 151924 Hom.: 5884 Cov.: 33

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.118

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.000965

Gnomad SAS AF: 0.0296

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.194

GnomAD3 exomes AF: 0.115 AC: 28677 AN: 249588 Hom.: 3227 AF XY: 0.107 AC XY: 14483 AN XY: 135502

Gnomad AFR exome AF: 0.504

Gnomad AMR exome AF: 0.0902

Gnomad ASJ exome AF: 0.142

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0293

Gnomad FIN exome AF: 0.116

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.124

GnomAD4 exome AF: 0.107 AC: 156378 AN: 1460350 Hom.: 12090 Cov.: 34 AF XY: 0.104 AC XY: 75345 AN XY: 726474

Gnomad4 AFR exome AF: 0.509

Gnomad4 AMR exome AF: 0.0977

Gnomad4 ASJ exome AF: 0.143

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0315

Gnomad4 FIN exome AF: 0.113

Gnomad4 NFE exome AF: 0.103

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.214 AC: 32464 AN: 152042 Hom.: 5899 Cov.: 33 AF XY: 0.208 AC XY: 15489 AN XY: 74346

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.150

Gnomad4 ASJ AF: 0.151

Gnomad4 EAS AF: 0.000967

Gnomad4 SAS AF: 0.0294

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.192

Alfa AF: 0.0861 Hom.: 166

Bravo AF: 0.231

Asia WGS AF: 0.0450 AC: 159 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-	- -

Tuberous sclerosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2018

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. -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	2.4
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs13332222; hg19: chr16-2138422; COSMIC: COSV51909741; COSMIC: COSV51909741;