rs1184908674

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000548.5(TSC2):​c.1993C>A​(p.Pro665Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P665A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

TSC2
NM_000548.5 missense

Scores

3
13
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.45
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TSC2NM_000548.5 linkuse as main transcriptc.1993C>A p.Pro665Thr missense_variant 19/42 ENST00000219476.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TSC2ENST00000219476.9 linkuse as main transcriptc.1993C>A p.Pro665Thr missense_variant 19/425 NM_000548.5 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1444818
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
717236
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.20
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.040
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.77
D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Uncertain
0.65
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Benign
1.9
L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-3.1
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.022
D;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G
Pathogenic
0.0
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
1.0
D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4
0.48
MutPred
0.36
Gain of phosphorylation at P665 (P = 0.0079);Gain of phosphorylation at P665 (P = 0.0079);Gain of phosphorylation at P665 (P = 0.0079);.;Gain of phosphorylation at P665 (P = 0.0079);Gain of phosphorylation at P665 (P = 0.0079);Gain of phosphorylation at P665 (P = 0.0079);Gain of phosphorylation at P665 (P = 0.0079);.;Gain of phosphorylation at P665 (P = 0.0079);Gain of phosphorylation at P665 (P = 0.0079);Gain of phosphorylation at P665 (P = 0.0079);Gain of phosphorylation at P665 (P = 0.0079);Gain of phosphorylation at P665 (P = 0.0079);.;
MVP
0.82
ClinPred
0.93
D
GERP RS
5.5
Varity_R
0.25
gMVP
0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2121831; API