16-2064392-C-T

Variant names:

• chr16-2064392-C-T
• rs397514991
• NM_000548.5:c.1564C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000548.5(TSC2):​c.1564C>T​(p.His522Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. H522P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1 O:1
• Conservation: PhyloP100: 3.85
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 16-2064392-C-T is Benign according to our data. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992. Variant chr16-2064392-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 64992.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1564C>T	p.His522Tyr	missense_variant	Exon 15 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1564C>T	p.His522Tyr	missense_variant	Exon 15 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 522 of the TSC2 protein (p.His522Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 22903760). ClinVar contains an entry for this variant (Variation ID: 64992). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt TSC2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect TSC2 function (PMID: 22903760). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Benign:1

Apr 03, 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 syndrome Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Uncertain	2.0	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PhyloP100		3.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.8	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Uncertain	0.35
Sift	Benign	0.23	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Uncertain	0.028	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.95	P;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.69
MutPred		0.45		Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);Gain of helix (P = 0.0854);.;
MVP		0.78
ClinPred		0.93	D
GERP RS		5.6
Varity_R		0.31
gMVP		0.32
Mutation Taster		=85/15	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: rs397514991; hg19: chr16-2114393; COSMIC: COSV54769030; COSMIC: COSV54769030;