16-2048698-C-T

Position:

• chr16-2048698-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000548.5(TSC2):​c.83C>T​(p.Pro28Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

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 (HGNC:):

ACMG classification

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=0.09016925).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.83C>T	p.Pro28Leu	missense_variant	2/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.83C>T	p.Pro28Leu	missense_variant	2/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 26, 2024

The p.P28L variant (also known as c.83C>T), located in coding exon 1 of the TSC2 gene, results from a C to T substitution at nucleotide position 83. The proline at codon 28 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Benign	0.86
DEOGEN2	Uncertain	0.49	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.37	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.090	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.90	L;.;.;L;L;.;.;L;L;.;.;L;.;.;.
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.3	N;.;.;.;N;.;.;N;N;.;.;.;.;.;N
REVEL	Benign	0.090
Sift	Benign	0.35	T;.;.;.;T;.;.;T;T;.;.;.;.;.;T
Sift4G	Benign	0.42	T;.;.;.;T;.;.;T;T;.;.;.;.;.;T
Polyphen		0.50	P;.;.;.;B;.;.;B;B;.;.;.;.;.;.
Vest4		0.27
MutPred		0.23		Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);Loss of glycosylation at P28 (P = 0.0235);.;
MVP		0.50
ClinPred		0.32	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.12
gMVP		0.25

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2098699;