rs45486196

Positions:

• chr16-2071924-G-A
• chr16-2071924-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000548.5(TSC2):​c.2087G>A​(p.Cys696Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C696R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.28

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 Pathogenic. Variant got 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2071923-T-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 16-2071924-G-A is Pathogenic according to our data. Variant chr16-2071924-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2071924-G-A is described in Lovd as [Pathogenic]. Variant chr16-2071924-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2087G>A	p.Cys696Tyr	missense_variant	19/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2087G>A	p.Cys696Tyr	missense_variant	19/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2020	This variant has been observed in several individuals affected with tuberous sclerosis (PMID: 10205261, Invitae). ClinVar contains an entry for this variant (Variation ID: 50106). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with tyrosine at codon 696 of the TSC2 protein (p.Cys696Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant has been reported to affect TSC2 protein function (PMID: 10205261, 15483652, 21309039). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Cys696 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been observed in individuals with TSC2-related conditions (PMID: 16981987), which suggests that this may be a clinically significant amino acid residue. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2016

The p.C696Y variant (also known as c.2087G>A), located in coding exon 18 of the TSC2 gene, results from a G to A substitution at nucleotide position 2087. The cysteine at codon 696 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was first reported in a patient who met diagnostic criteria for tuberous sclerosis complex (Jones AC et al. Am. J. Hum. Genet., 1999 May;64:1305-15). In addition, functional studies indicate that this variant disrupts the tuberin-hamartin interaction, inhibits phosphorylation, and does not stimulate the rheb GTPase activity (Nellist M et al. Hum. Mol. Genet., 2001 Dec;10:2889-98; Nellist M et al. Eur. J. Hum. Genet., 2005 Jan;13:59-68). This variant was previously reported in the SNPDatabase as rs45486196, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.89	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-8.1	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.85
Sift	Benign	0.13	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.91
MutPred		0.95		Loss of catalytic residue at L697 (P = 0.0265);Loss of catalytic residue at L697 (P = 0.0265);Loss of catalytic residue at L697 (P = 0.0265);.;Loss of catalytic residue at L697 (P = 0.0265);Loss of catalytic residue at L697 (P = 0.0265);Loss of catalytic residue at L697 (P = 0.0265);Loss of catalytic residue at L697 (P = 0.0265);.;Loss of catalytic residue at L697 (P = 0.0265);Loss of catalytic residue at L697 (P = 0.0265);Loss of catalytic residue at L697 (P = 0.0265);Loss of catalytic residue at L697 (P = 0.0265);Loss of catalytic residue at L697 (P = 0.0265);.;
MVP		0.92
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.78

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: rs45486196; hg19: chr16-2121925;