rs45517238

chr16-2074320-C-Achr16-2074320-C-Gchr16-2074320-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM5 BP4_Moderate BP6 BS2

The NM_000548.5(TSC2):c.2476C>A(p.Leu826Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00135 in 1,613,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L826P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:20 O:1
• Conservation: PhyloP100: 0.644

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 Likely_benign. Variant got -5 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2074321-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 49751.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.09538305).
• BP6: Variant 16-2074320-C-A is Benign according to our data. Variant chr16-2074320-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41732.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=7, Uncertain_significance=1, not_provided=1}. Variant chr16-2074320-C-A is described in Lovd as [Likely_benign]. Variant chr16-2074320-C-A is described in Lovd as [Benign]. Variant chr16-2074320-C-A is described in Lovd as [Pathogenic].
• BS2: High AC in GnomAd at 105 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.2476C>A	p.Leu826Met	missense_variant	22/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.2476C>A	p.Leu826Met	missense_variant	22/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152254 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000679 AC: 170 AN: 250542 Hom.: 0 AF XY: 0.000730 AC XY: 99 AN XY: 135688

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000140

Gnomad NFE exome AF: 0.00120

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.00142 AC: 2077 AN: 1460694 Hom.: 0 Cov.: 31 AF XY: 0.00142 AC XY: 1031 AN XY: 726646

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000765

Gnomad4 NFE exome AF: 0.00177

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152372 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74512

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000637 Hom.: 0

Bravo AF: 0.000756

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000560 AC: 68

EpiCase AF: 0.000818

EpiControl AF: 0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:20 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:7

Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Oct 05, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	TSC2: PM5, BS1 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

not specified Uncertain:1 Benign:5

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 23, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 25, 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: 0.1% (62/65736) European chromsomes; ClinVar: 4 labs classify as LB. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Tuberous sclerosis 2 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 10, 2022	- -

Tuberous sclerosis syndrome Benign:2 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 14, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 27, 2018	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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.47	N
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.095	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	1.7	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.64
Sift	Uncertain	0.012	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.049	D;.;.;D;.;D;.;.;D;T;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;P;D;.;.;.;.;.
Vest4		0.78
MVP		0.82
ClinPred		0.065	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.49

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: rs45517238; hg19: chr16-2124321; COSMIC: COSV104375750; COSMIC: COSV104375750;