16-2086623-T-C

Position:

• chr16-2086623-T-C

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.4850-109T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.186 in 1,538,084 control chromosomes in the GnomAD database, including 33,023 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (8001 hom., cov: 33)
  • Exomes 𝑓: 0.18 (25022 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -3.40

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]

TSC2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 16-2086623-T-C is Benign according to our data. Variant chr16-2086623-T-C is described in ClinVar as [Benign]. Clinvar id is 65253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2086623-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.535 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4850-109T>C		intron_variant		ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4850-109T>C		intron_variant		5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.275 AC: 41725 AN: 151976 Hom.: 7964 Cov.: 33

Gnomad AFR AF: 0.540

Gnomad AMI AF: 0.0978

Gnomad AMR AF: 0.198

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0928

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.249

GnomAD4 exome AF: 0.177 AC: 244845 AN: 1385990 Hom.: 25022 AF XY: 0.173 AC XY: 118993 AN XY: 686782

Gnomad4 AFR exome AF: 0.550

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.242

Gnomad4 EAS exome AF: 0.000241

Gnomad4 SAS exome AF: 0.0962

Gnomad4 FIN exome AF: 0.223

Gnomad4 NFE exome AF: 0.176

Gnomad4 OTH exome AF: 0.191

GnomAD4 genome AF: 0.275 AC: 41810 AN: 152094 Hom.: 8001 Cov.: 33 AF XY: 0.272 AC XY: 20214 AN XY: 74354

Gnomad4 AFR AF: 0.541

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0925

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.247

Alfa AF: 0.157 Hom.: 478

Bravo AF: 0.284

Asia WGS AF: 0.0830 AC: 291 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jul 31, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy, Progressive Myoclonus Epilepsy and Abnormal Movements and Neurodegeneration with brain iron accumulation. Number of patients: 21. Only high quality variants are reported. -

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	-0.92
CADD	Benign	0.82
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs13335638; hg19: chr16-2136624;