16-2084259-C-T

Variant names:

• chr16-2084259-C-T
• rs45517326
• NM_000548.5:c.4037C>T

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000548.5(TSC2):​c.4037C>T​(p.Ser1346Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000964 in 1,453,008 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. S1346W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.808
• Publications: 5 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.092668295).
• BP6: Variant 16-2084259-C-T is Benign according to our data. Variant chr16-2084259-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 486606.
• BS2: High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4037C>T	p.Ser1346Leu	missense_variant	Exon 34 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4037C>T	p.Ser1346Leu	missense_variant	Exon 34 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000856 AC: 2 AN: 233586 AF XY: 0.0000157

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000206

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000964 AC: 14 AN: 1453008 Hom.: 0 Cov.: 33 AF XY: 0.0000111 AC XY: 8 AN XY: 722074

African (AFR) AF: 0.0000301 AC: 1 AN: 33252

American (AMR) AF: 0.00 AC: 0 AN: 44162

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 26000

East Asian (EAS) AF: 0.00 AC: 0 AN: 39260

South Asian (SAS) AF: 0.00 AC: 0 AN: 84872

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00000993 AC: 11 AN: 1108118

Other (OTH) AF: 0.0000167 AC: 1 AN: 60032

GnomAD4 genome Cov.: 34

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000830 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Dec 17, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jan 18, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Tuberous sclerosis 2 Benign:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Uncertain:1

Jul 20, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces serine with leucine at codon 1346 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 2/233586 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.093	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		0.81
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.55
Sift	Benign	0.088	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.073	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.0020	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.32
MutPred		0.21		Loss of phosphorylation at S1346 (P = 0.0096);.;.;.;.;.;.;Loss of phosphorylation at S1346 (P = 0.0096);.;.;.;.;.;.;.;
MVP		0.98
ClinPred		0.068	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.094
gMVP		0.27
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs45517326; hg19: chr16-2134260;