rs7187438

Positions:

• chr16-2070401-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.1717-55T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,612,486 control chromosomes in the GnomAD database, including 103,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15472 hom., cov: 33)
  • Exomes 𝑓: 0.34 (88204 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: -0.572

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=-0.91).
• BP6: Variant 16-2070401-T-C is Benign according to our data. Variant chr16-2070401-T-C is described in ClinVar as [Benign]. Clinvar id is 65157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2070401-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.665 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1717-55T>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.1717-55T>C		intron_variant		5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64283 AN: 151948 Hom.: 15446 Cov.: 33

Gnomad AFR AF: 0.672

Gnomad AMI AF: 0.457

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.254

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.340

Gnomad OTH AF: 0.440

GnomAD4 exome AF: 0.341 AC: 497687 AN: 1460420 Hom.: 88204 AF XY: 0.338 AC XY: 245381 AN XY: 726492

Gnomad4 AFR exome AF: 0.693

Gnomad4 AMR exome AF: 0.225

Gnomad4 ASJ exome AF: 0.396

Gnomad4 EAS exome AF: 0.263

Gnomad4 SAS exome AF: 0.265

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.362

GnomAD4 genome AF: 0.423 AC: 64348 AN: 152066 Hom.: 15472 Cov.: 33 AF XY: 0.417 AC XY: 31016 AN XY: 74334

Gnomad4 AFR AF: 0.672

Gnomad4 AMR AF: 0.325

Gnomad4 ASJ AF: 0.393

Gnomad4 EAS AF: 0.237

Gnomad4 SAS AF: 0.254

Gnomad4 FIN AF: 0.298

Gnomad4 NFE AF: 0.340

Gnomad4 OTH AF: 0.435

Alfa AF: 0.367 Hom.: 10349

Bravo AF: 0.442

Asia WGS AF: 0.255 AC: 888 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, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 40. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 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

- -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.2
DANN	Benign	0.27

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: rs7187438; hg19: chr16-2120402; COSMIC: COSV54767291; COSMIC: COSV54767291;