rs1489548085

Positions:

• chr16-2072979-A-C
• chr16-2072979-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000548.5(TSC2):​c.2351A>C​(p.Lys784Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.27

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26704693).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2351A>C	p.Lys784Thr	missense_variant	21/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2351A>C	p.Lys784Thr	missense_variant	21/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461106 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726826

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 06, 2023

In 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 467937). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 784 of the TSC2 protein (p.Lys784Thr). -

TSC2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 24, 2024

The TSC2 c.2351A>C variant is predicted to result in the amino acid substitution p.Lys784Thr. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/467937/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Isolated focal cortical dysplasia type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 15, 2024

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 14, 2023

The p.K784T variant (also known as c.2351A>C), located in coding exon 20 of the TSC2 gene, results from an A to C substitution at nucleotide position 2351. The lysine at codon 784 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.45
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Benign	19
DANN	Benign	0.90
DEOGEN2	Uncertain	0.46	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.60
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.27	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.74	N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.37	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.53
Sift	Benign	0.22	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Uncertain	0.054	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.51	P;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.49
MutPred		0.53		Loss of ubiquitination at K784 (P = 0.0071);Loss of ubiquitination at K784 (P = 0.0071);Loss of ubiquitination at K784 (P = 0.0071);.;Loss of ubiquitination at K784 (P = 0.0071);Loss of ubiquitination at K784 (P = 0.0071);Loss of ubiquitination at K784 (P = 0.0071);Loss of ubiquitination at K784 (P = 0.0071);.;Loss of ubiquitination at K784 (P = 0.0071);Loss of ubiquitination at K784 (P = 0.0071);Loss of ubiquitination at K784 (P = 0.0071);Loss of ubiquitination at K784 (P = 0.0071);Loss of ubiquitination at K784 (P = 0.0071);.;
MVP		0.86
ClinPred		0.24	T
GERP RS		-0.52
Varity_R		0.10
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1489548085; hg19: chr16-2122980;