rs137854239

Positions:

• chr16-2084980-CCTT-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_000548.5(TSC2):​c.4527_4529del​(p.Phe1510del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00521 in 1,613,366 control chromosomes in the GnomAD database, including 44 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1508P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0054 (41 hom.)
• Consequence: TSC2 NM_000548.5 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:22 O:3
• Conservation: PhyloP100: 6.16

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 -8 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000548.5. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 16-2084980-CCTT-C is Benign according to our data. Variant chr16-2084980-CCTT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 49302.We mark this variant Likely_benign, oryginal submissions are: {not_provided=3, Likely_benign=5, Uncertain_significance=1, Benign=14}. Variant chr16-2084980-CCTT-C is described in Lovd as [Benign]. Variant chr16-2084980-CCTT-C is described in Lovd as [Likely_benign]. Variant chr16-2084980-CCTT-C is described in Lovd as [Pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00362 (552/152350) while in subpopulation SAS AF= 0.00911 (44/4828). AF 95% confidence interval is 0.00698. There are 3 homozygotes in gnomad4. There are 281 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 552 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.4527_4529del	p.Phe1510del	inframe_deletion	35/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.4527_4529del	p.Phe1510del	inframe_deletion	35/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 552 AN: 152232 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.0302

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.00612

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00394

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00539 AC: 1350 AN: 250376 Hom.: 8 AF XY: 0.00594 AC XY: 807 AN XY: 135754

Gnomad AFR exome AF: 0.000681

Gnomad AMR exome AF: 0.00119

Gnomad ASJ exome AF: 0.0336

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00951

Gnomad FIN exome AF: 0.00476

Gnomad NFE exome AF: 0.00475

Gnomad OTH exome AF: 0.00491

GnomAD4 exome AF: 0.00538 AC: 7858 AN: 1461016 Hom.: 41 AF XY: 0.00562 AC XY: 4082 AN XY: 726798

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.0338

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00991

Gnomad4 FIN exome AF: 0.00485

Gnomad4 NFE exome AF: 0.00475

Gnomad4 OTH exome AF: 0.00745

GnomAD4 genome AF: 0.00362 AC: 552 AN: 152350 Hom.: 3 Cov.: 33 AF XY: 0.00377 AC XY: 281 AN XY: 74500

Gnomad4 AFR AF: 0.000649

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.0302

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.00612

Gnomad4 NFE AF: 0.00394

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00787 Hom.: 2

Bravo AF: 0.00334

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00528

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:22 Other:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:9 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 17, 2021	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2013	The variant is found in EPILEPSY,INFANT-EPI panel(s). -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 07, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 28, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital	Jul 17, 2017	BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.9% (155/16504) South Asian chromosomes. ClinVar: 3 labs classify as benign/likely benign -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 24, 2022	- -

Tuberous sclerosis 2 Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 25, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 20, 2022	- -

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 28, 2017	- -
Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 23, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	TSC2: PM4:Supporting, BS2 -

Tuberous sclerosis syndrome Benign:1 Other:2

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	Apr 06, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	Apr 06, 2011	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 20, 2017	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 24, 2020	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs137854239; hg19: chr16-2134981;