rs45486599

chr16-2064285-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000548.5(TSC2):c.1457A>T(p.Asn486Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. N486K) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 6.05

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.1457A>T	p.Asn486Ile	missense_variant	15/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.1457A>T	p.Asn486Ile	missense_variant	15/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2021

This sequence change replaces asparagine with isoleucine at codon 486 of the TSC2 protein (p.Asn486Ile). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and isoleucine. 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: 49788). This variant is also known as c.1475A>T. This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 10732801). This variant is not present in population databases (ExAC no frequency). -

Tuberous sclerosis syndrome Other:1

not provided, no classification provided

curation

Tuberous sclerosis database (TSC2)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	23
Dann	Uncertain	0.98
DEOGEN2	Pathogenic	0.86	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	0.042
Eigen_PC	Benign	0.12
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.045	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.4	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.7	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0050	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.010	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.86
MutPred		0.82		Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);.;Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);.;Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);Gain of sheet (P = 0.0166);.;
MVP		0.77
ClinPred		0.99	D
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.55
gMVP		0.35

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: rs45486599; hg19: chr16-2114286;