chr16-2062649-CTCTG-C

Variant names:

• chr16-2062649-CTCTG-C
• rs137854304
• NM_000548.5:c.1361+54_1361+57delTCTG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_000548.5(TSC2):​c.1361+54_1361+57delTCTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,547,758 control chromosomes in the GnomAD database, including 16 homozygotes. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (16 hom.)
• Consequence: TSC2 NM_000548.5 intron
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.398
• Publications: 2 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0024 (365/152348) while in subpopulation NFE AF = 0.00393 (267/68022). AF 95% confidence interval is 0.00354. There are 0 homozygotes in GnomAd4. There are 165 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 365 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	NM_000548.5	MANE Select	c.1361+54_1361+57delTCTG		intron	N/A	NP_000539.2
	TSC2	NM_001406663.1		c.1361+54_1361+57delTCTG		intron	N/A	NP_001393592.1
	TSC2	NM_001114382.3		c.1361+54_1361+57delTCTG		intron	N/A	NP_001107854.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSC2	ENST00000219476.9	TSL:5 MANE Select	c.1361+50_1361+53delTCTG		intron	N/A	ENSP00000219476.3
	TSC2	ENST00000350773.9	TSL:1	c.1361+50_1361+53delTCTG		intron	N/A	ENSP00000344383.4
	TSC2	ENST00000401874.7	TSL:1	c.1361+50_1361+53delTCTG		intron	N/A	ENSP00000384468.2

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 365 AN: 152230 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00314

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00392

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00229 AC: 404 AN: 176058 AF XY: 0.00223

Gnomad AFR exome AF: 0.000673

Gnomad AMR exome AF: 0.00303

Gnomad ASJ exome AF: 0.000451

Gnomad EAS exome AF: 0.0000750

Gnomad FIN exome AF: 0.000242

Gnomad NFE exome AF: 0.00394

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00380 AC: 5297 AN: 1395410 Hom.: 16 AF XY: 0.00366 AC XY: 2531 AN XY: 690820

African (AFR) AF: 0.000688 AC: 22 AN: 31966

American (AMR) AF: 0.00317 AC: 120 AN: 37814

Ashkenazi Jewish (ASJ) AF: 0.000316 AC: 8 AN: 25316

East Asian (EAS) AF: 0.0000537 AC: 2 AN: 37266

South Asian (SAS) AF: 0.000348 AC: 28 AN: 80494

European-Finnish (FIN) AF: 0.000243 AC: 12 AN: 49408

Middle Eastern (MID) AF: 0.00112 AC: 5 AN: 4468

European-Non Finnish (NFE) AF: 0.00458 AC: 4908 AN: 1070758

Other (OTH) AF: 0.00331 AC: 192 AN: 57920

GnomAD4 genome AF: 0.00240 AC: 365 AN: 152348 Hom.: 0 Cov.: 33 AF XY: 0.00221 AC XY: 165 AN XY: 74492

African (AFR) AF: 0.000769 AC: 32 AN: 41588

American (AMR) AF: 0.00314 AC: 48 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10628

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00393 AC: 267 AN: 68022

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00302 Hom.: 0

Bravo AF: 0.00282

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Tuberous sclerosis syndrome Other:1

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism

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: rs137854304; hg19: chr16-2112650; COSMIC: COSV104587100;