rs30259

Variant names:

• chr16-2083900-C-T
• rs30259
• NM_000548.5:c.4005+84C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000548.5(TSC2):​c.4005+84C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0854 in 1,518,862 control chromosomes in the GnomAD database, including 6,158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.064 (435 hom., cov: 34)
  • Exomes 𝑓: 0.088 (5723 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.184
• Publications: 15 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: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 16-2083900-C-T is Benign according to our data. Variant chr16-2083900-C-T is described in ClinVar as [Benign]. Clinvar id is 1266887.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0926 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4005+84C>T		intron_variant	Intron 33 of 41	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4005+84C>T		intron_variant	Intron 33 of 41	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes AF: 0.0639 AC: 9725 AN: 152102 Hom.: 435 Cov.: 34

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.133

Gnomad AMR AF: 0.0539

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.0370

Gnomad SAS AF: 0.0505

Gnomad FIN AF: 0.0763

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0945

Gnomad OTH AF: 0.0641

GnomAD4 exome AF: 0.0878 AC: 120006 AN: 1366642 Hom.: 5723 AF XY: 0.0873 AC XY: 58626 AN XY: 671510

African (AFR) AF: 0.0145 AC: 459 AN: 31608

American (AMR) AF: 0.0372 AC: 1179 AN: 31692

Ashkenazi Jewish (ASJ) AF: 0.0737 AC: 1631 AN: 22120

East Asian (EAS) AF: 0.0538 AC: 2054 AN: 38146

South Asian (SAS) AF: 0.0504 AC: 3750 AN: 74426

European-Finnish (FIN) AF: 0.0863 AC: 3385 AN: 39212

Middle Eastern (MID) AF: 0.0596 AC: 248 AN: 4158

European-Non Finnish (NFE) AF: 0.0961 AC: 102676 AN: 1068618

Other (OTH) AF: 0.0816 AC: 4624 AN: 56662

GnomAD4 genome AF: 0.0638 AC: 9717 AN: 152220 Hom.: 435 Cov.: 34 AF XY: 0.0633 AC XY: 4710 AN XY: 74416

African (AFR) AF: 0.0165 AC: 684 AN: 41546

American (AMR) AF: 0.0538 AC: 824 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3468

East Asian (EAS) AF: 0.0369 AC: 191 AN: 5176

South Asian (SAS) AF: 0.0499 AC: 241 AN: 4826

European-Finnish (FIN) AF: 0.0763 AC: 809 AN: 10602

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0945 AC: 6423 AN: 67976

Other (OTH) AF: 0.0629 AC: 133 AN: 2114

Alfa AF: 0.0815 Hom.: 559

Bravo AF: 0.0581

Asia WGS AF: 0.0390 AC: 134 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 25, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.6
DANN	Benign	0.36
PhyloP100		0.18
Mutation Taster		=100/0	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: rs30259; hg19: chr16-2133901; COSMIC: COSV104375821;