NM_000548.5:c.2742G>C

Variant summary

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

The NM_000548.5(TSC2):​c.2742G>C​(p.Lys914Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K914Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

TSC2
NM_000548.5 missense, splice_region

Scores

5
12
2
Splicing: ADA: 1.000
2

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 9.69
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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain 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 chr16-2076168-AA-G is described in ClinVar as [Pathogenic]. Clinvar id is 964914.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC2NM_000548.5 linkc.2742G>C p.Lys914Asn missense_variant, splice_region_variant Exon 24 of 42 ENST00000219476.9 NP_000539.2 P49815-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TSC2ENST00000219476.9 linkc.2742G>C p.Lys914Asn missense_variant, splice_region_variant Exon 24 of 42 5 NM_000548.5 ENSP00000219476.3 P49815-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

Tuberous sclerosis syndrome Other:1
-
Tuberous sclerosis database (TSC2)
Significance: not provided
Review Status: no classification provided
Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.16
D
BayesDel_noAF
Uncertain
0.0
CADD
Pathogenic
36
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.77
D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen
Uncertain
0.61
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.87
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
0.43
D
MetaRNN
Uncertain
0.51
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.71
D
MutationAssessor
Uncertain
2.2
M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-2.5
D;.;.;D;.;N;.;.;D;D;.;.;.;.;N
REVEL
Uncertain
0.58
Sift
Benign
0.20
T;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G
Uncertain
0.017
D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen
0.99
D;.;.;.;D;D;.;.;D;P;.;.;.;.;.
Vest4
0.80
MutPred
0.33
Loss of methylation at K914 (P = 0.0143);Loss of methylation at K914 (P = 0.0143);Loss of methylation at K914 (P = 0.0143);.;Loss of methylation at K914 (P = 0.0143);Loss of methylation at K914 (P = 0.0143);Loss of methylation at K914 (P = 0.0143);Loss of methylation at K914 (P = 0.0143);.;Loss of methylation at K914 (P = 0.0143);Loss of methylation at K914 (P = 0.0143);Loss of methylation at K914 (P = 0.0143);Loss of methylation at K914 (P = 0.0143);Loss of methylation at K914 (P = 0.0143);.;
MVP
0.96
ClinPred
0.95
D
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.46
gMVP
0.67

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.57
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.36
Position offset: 34
DS_DL_spliceai
0.57
Position offset: 0

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: rs137854877; hg19: chr16-2126171; API