16-2086749-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000548.5(TSC2):​c.4867A>G​(p.Thr1623Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. T1623S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

TSC2
NM_000548.5 missense

Scores

14
4
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.24
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 362 pathogenic changes around while only 144 benign (72%) in NM_000548.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr16-2086750-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TSC2NM_000548.5 linkuse as main transcriptc.4867A>G p.Thr1623Ala missense_variant 38/42 ENST00000219476.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.4867A>G p.Thr1623Ala missense_variant 38/425 NM_000548.5 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMar 06, 2019In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TSC2-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 1623 of the TSC2 protein (p.Thr1623Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.81
BayesDel_addAF
Pathogenic
0.56
D
BayesDel_noAF
Pathogenic
0.57
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.98
D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.79
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.3
M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-4.5
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0020
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Pathogenic
0.0
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
1.0
D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4
0.95
MutPred
0.85
Loss of glycosylation at T1623 (P = 0.0445);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP
0.99
ClinPred
1.0
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.93
gMVP
0.92

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.

Other links and lift over

dbSNP: rs749501410; hg19: chr16-2136750; API