rs17654678

Variant names:

• chr16-2064643-T-G
• rs17654678
• NM_000548.5:c.1599+216T>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000548.5(TSC2):​c.1599+216T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0889 in 716,704 control chromosomes in the GnomAD database, including 3,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.074 (587 hom., cov: 33)
  • Exomes 𝑓: 0.093 (3002 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.737

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 16-2064643-T-G is Benign according to our data. Variant chr16-2064643-T-G is described in ClinVar as [Benign]. Clinvar id is 1292780.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1599+216T>G		intron_variant	Intron 15 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1599+216T>G		intron_variant	Intron 15 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0743 AC: 11305 AN: 152152 Hom.: 587 Cov.: 33

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.0466

Gnomad ASJ AF: 0.0423

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0552

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.113

Gnomad OTH AF: 0.0635

GnomAD4 exome AF: 0.0929 AC: 52446 AN: 564434 Hom.: 3002 Cov.: 7 AF XY: 0.0925 AC XY: 27089 AN XY: 292950

Gnomad4 AFR exome AF: 0.0171

Gnomad4 AMR exome AF: 0.0352

Gnomad4 ASJ exome AF: 0.0422

Gnomad4 EAS exome AF: 0.000491

Gnomad4 SAS exome AF: 0.0589

Gnomad4 FIN exome AF: 0.144

Gnomad4 NFE exome AF: 0.112

Gnomad4 OTH exome AF: 0.0806

GnomAD4 genome AF: 0.0742 AC: 11300 AN: 152270 Hom.: 587 Cov.: 33 AF XY: 0.0737 AC XY: 5488 AN XY: 74448

Gnomad4 AFR AF: 0.0186

Gnomad4 AMR AF: 0.0465

Gnomad4 ASJ AF: 0.0423

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0551

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.113

Gnomad4 OTH AF: 0.0624

Alfa AF: 0.0956 Hom.: 397

Bravo AF: 0.0633

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.38
DANN	Benign	0.44

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: rs17654678; hg19: chr16-2114644;