rs17654678

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000548.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.1599+216T>G		intron	N/A	NP_000539.2	P49815-1
	TSC2	NM_001406663.1		c.1599+216T>G		intron	N/A	NP_001393592.1	A0A2R8Y6C9
	TSC2	NM_001114382.3		c.1599+216T>G		intron	N/A	NP_001107854.1	P49815-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1599+216T>G		intron	N/A	ENSP00000219476.3	P49815-1
	TSC2	ENST00000350773.9	TSL:1	c.1599+216T>G		intron	N/A	ENSP00000344383.4	P49815-4
	TSC2	ENST00000401874.7	TSL:1	c.1599+216T>G		intron	N/A	ENSP00000384468.2	P49815-5

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

African (AFR) AF: 0.0171 AC: 261 AN: 15306

American (AMR) AF: 0.0352 AC: 893 AN: 25378

Ashkenazi Jewish (ASJ) AF: 0.0422 AC: 635 AN: 15052

East Asian (EAS) AF: 0.000491 AC: 15 AN: 30536

South Asian (SAS) AF: 0.0589 AC: 3015 AN: 51188

European-Finnish (FIN) AF: 0.144 AC: 4055 AN: 28170

Middle Eastern (MID) AF: 0.0317 AC: 70 AN: 2206

European-Non Finnish (NFE) AF: 0.112 AC: 41106 AN: 366860

Other (OTH) AF: 0.0806 AC: 2396 AN: 29738

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

African (AFR) AF: 0.0186 AC: 774 AN: 41570

American (AMR) AF: 0.0465 AC: 712 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0423 AC: 147 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5174

South Asian (SAS) AF: 0.0551 AC: 266 AN: 4830

European-Finnish (FIN) AF: 0.136 AC: 1439 AN: 10602

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.113 AC: 7684 AN: 67996

Other (OTH) AF: 0.0624 AC: 132 AN: 2116

Alfa AF: 0.0973 Hom.: 615

Bravo AF: 0.0633

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.38
DANN	Benign	0.44
PhyloP100		-0.74
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs17654678; hg19: chr16-2114644;