chr16-2071851-C-T

Position:

chr16-2071851-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000548.5(TSC2):c.2014C>T(p.Pro672Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,234 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. P672L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 0.562

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 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19490254).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.2014C>T	p.Pro672Ser	missense_variant	19/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.2014C>T	p.Pro672Ser	missense_variant	19/42	5	NM_000548.5		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000579

AC:

AN:

172620

Hom.:

AF XY:

0.00

AC XY:

AN XY:

94768

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000749

Gnomad SAS 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:

7.03e-7

AC:

AN:

1422234

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

704242

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.15e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis 2

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 12, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 04, 2024

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 03, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The p.P672S variant (also known as c.2014C>T), located in coding exon 18 of the TSC2 gene, results from a C to T substitution at nucleotide position 2014. The proline at codon 672 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.066

BayesDel_noAF

Benign

-0.14

CADD

Benign

7.7

DANN

Benign

0.75

DEOGEN2

Uncertain

0.59

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

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.85

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

M_CAP

Benign

0.068

MetaRNN

Benign

0.19

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

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.1

L;.;.;.;L;L;.;.;.;L;.;L;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N

PrimateAI

Benign

0.37

PROVEAN

Uncertain

-2.5

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

REVEL

Uncertain

0.43

Sift

Benign

0.073

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

Sift4G

Uncertain

0.055

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

Polyphen

0.0

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

Vest4

0.26

MutPred

0.32

Gain of phosphorylation at P672 (P = 0.0124);Gain of phosphorylation at P672 (P = 0.0124);Gain of phosphorylation at P672 (P = 0.0124);.;Gain of phosphorylation at P672 (P = 0.0124);Gain of phosphorylation at P672 (P = 0.0124);Gain of phosphorylation at P672 (P = 0.0124);Gain of phosphorylation at P672 (P = 0.0124);.;Gain of phosphorylation at P672 (P = 0.0124);Gain of phosphorylation at P672 (P = 0.0124);Gain of phosphorylation at P672 (P = 0.0124);Gain of phosphorylation at P672 (P = 0.0124);Gain of phosphorylation at P672 (P = 0.0124);.;

MVP

0.96

ClinPred

0.038

GERP RS

2.0

Varity_R

0.041

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over