rs753336580

chr16-2088259-C-Achr16-2088259-C-Gchr16-2088259-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000548.5(TSC2):c.5193C>A(p.Asn1731Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,196 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. N1731D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 1.23

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 360 pathogenic changes around while only 144 benign (71%) in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.5193C>A	p.Asn1731Lys	missense_variant	41/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.5193C>A	p.Asn1731Lys	missense_variant	41/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459196 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725886

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 05, 2024	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1731 of the TSC2 protein (p.Asn1731Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 468145). 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 with a negative predictive value of 95%. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 19, 2024

The p.N1731K variant (also known as c.5193C>A), located in coding exon 40 of the TSC2 gene, results from a C to A substitution at nucleotide position 5193. The asparagine at codon 1731 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.45	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	0.76	N;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.7	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.60
Sift	Benign	0.19	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Uncertain	0.0050	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.56
MutPred		0.49		Gain of ubiquitination at N1731 (P = 0.0162);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.80
ClinPred		0.84	D
GERP RS		2.2
Varity_R		0.37
gMVP		0.66

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

Other links and lift over

dbSNP: rs753336580; hg19: chr16-2138260;