rs17135764

chr16-2061778-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.1120-93T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.598 in 1,600,276 control chromosomes in the GnomAD database, including 288,711 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.57 (25175 hom., cov: 32)
  • Exomes 𝑓: 0.60 (263536 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: -3.24

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=-0.89).
• BP6: Variant 16-2061778-T-C is Benign according to our data. Variant chr16-2061778-T-C is described in ClinVar as [Benign]. Clinvar id is 49143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2061778-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.785 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.1120-93T>C		intron_variant		ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.1120-93T>C		intron_variant		5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.570 AC: 86516 AN: 151802 Hom.: 25141 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.698

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.613

Gnomad EAS AF: 0.806

Gnomad SAS AF: 0.662

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.620

Gnomad NFE AF: 0.603

Gnomad OTH AF: 0.578

GnomAD4 exome AF: 0.601 AC: 870903 AN: 1448356 Hom.: 263536 Cov.: 28 AF XY: 0.604 AC XY: 435283 AN XY: 720816

Gnomad4 AFR exome AF: 0.451

Gnomad4 AMR exome AF: 0.665

Gnomad4 ASJ exome AF: 0.609

Gnomad4 EAS exome AF: 0.780

Gnomad4 SAS exome AF: 0.657

Gnomad4 FIN exome AF: 0.581

Gnomad4 NFE exome AF: 0.593

Gnomad4 OTH exome AF: 0.608

GnomAD4 genome AF: 0.570 AC: 86589 AN: 151920 Hom.: 25175 Cov.: 32 AF XY: 0.572 AC XY: 42463 AN XY: 74274

Gnomad4 AFR AF: 0.452

Gnomad4 AMR AF: 0.607

Gnomad4 ASJ AF: 0.613

Gnomad4 EAS AF: 0.806

Gnomad4 SAS AF: 0.663

Gnomad4 FIN AF: 0.575

Gnomad4 NFE AF: 0.603

Gnomad4 OTH AF: 0.583

Alfa AF: 0.597 Hom.: 33955

Bravo AF: 0.566

Asia WGS AF: 0.746 AC: 2588 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 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 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.050
Dann	Benign	0.34

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: rs17135764; hg19: chr16-2111779; COSMIC: COSV54772015; COSMIC: COSV54772015;