16-2074208-G-A

Position:

chr16-2074208-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM5BP4_ModerateBP6BS2

The NM_000548.5(TSC2):c.2364G>A(p.Met788Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000117 in 1,459,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 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. M788R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TSC2
NM_000548.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 2.55

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr16-2074207-T-G is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.1780904).

BP6

Variant 16-2074208-G-A is Benign according to our data. Variant chr16-2074208-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 406123.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

BS2

High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5 linkuse as main transcript	c.2364G>A	p.Met788Ile	missense_variant	22/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9 linkuse as main transcript	c.2364G>A	p.Met788Ile	missense_variant	22/42	5	NM_000548.5	ENSP00000219476		P49815-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000803

AC:

AN:

248996

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000179

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000117

AC:

AN:

1459086

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

725902

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:

0.0000153

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Tuberous sclerosis syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Apr 27, 2023

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2021

The p.M788I variant (also known as c.2364G>A), located in coding exon 21 of the TSC2 gene, results from a G to A substitution at nucleotide position 2364. The methionine at codon 788 is replaced by isoleucine, an amino acid with highly 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Tuberous sclerosis 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Uncertain

0.055

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.41

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

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.26

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.84

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

M_CAP

Benign

0.061

MetaRNN

Benign

0.18

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

MetaSVM

Benign

-0.75

MutationAssessor

Benign

-0.070

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

MutationTaster

Benign

1.0

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

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.23

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

REVEL

Uncertain

0.35

Sift

Benign

0.070

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

Sift4G

Benign

0.11

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

Polyphen

0.0

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

Vest4

0.36

MutPred

0.50

Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);.;Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);.;Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);.;

MVP

0.77

ClinPred

0.44

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.37

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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