16-2071851-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000548.5(TSC2):c.2014C>G(p.Pro672Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P672S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.562

Publications

2 publications found

Variant links:

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

TSC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17574185).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5 link	c.2014C>G	p.Pro672Ala	missense_variant	Exon 19 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 link	c.2014C>G	p.Pro672Ala	missense_variant	Exon 19 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:1

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 672 of the TSC2 protein (p.Pro672Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 535909). 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%. 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. -

not provided

Uncertain:1

Mar 23, 2022

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Hereditary cancer-predisposing syndrome

Uncertain:1

Jan 27, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P672A variant (also known as c.2014C>G), located in coding exon 18 of the TSC2 gene, results from a C to G substitution at nucleotide position 2014. The proline at codon 672 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Benign

-0.20

CADD

Benign

4.9

(source)

DANN

Benign

0.72

DEOGEN2

Uncertain

0.69

D;.;.;.;.;.;.;.;.;.;.;.;D;.;D

Eigen

Benign

-0.67

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.88

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.18

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

0.20

N;.;.;.;N;N;.;.;.;N;.;N;.;.;.

PhyloP100

0.56

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-2.5

D;.;.;N;.;D;.;.;N;D;.;.;.;.;D

REVEL

Uncertain

0.34

Sift

Benign

0.50

T;.;.;T;.;T;.;.;T;T;.;.;.;.;T

Sift4G

Benign

0.29

T;.;.;T;.;T;.;.;T;T;.;.;.;.;T

Polyphen

0.0080

B;.;.;.;B;B;.;.;B;B;.;.;.;.;.

Vest4

0.30

MutPred

0.36

Loss of glycosylation at P672 (P = 0.0057);Loss of glycosylation at P672 (P = 0.0057);Loss of glycosylation at P672 (P = 0.0057);.;Loss of glycosylation at P672 (P = 0.0057);Loss of glycosylation at P672 (P = 0.0057);Loss of glycosylation at P672 (P = 0.0057);Loss of glycosylation at P672 (P = 0.0057);.;Loss of glycosylation at P672 (P = 0.0057);Loss of glycosylation at P672 (P = 0.0057);Loss of glycosylation at P672 (P = 0.0057);Loss of glycosylation at P672 (P = 0.0057);Loss of glycosylation at P672 (P = 0.0057);.;

MVP

0.88

ClinPred

0.15

GERP RS

2.0

Varity_R

0.043

gMVP

0.36

Mutation Taster

=92/8

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over