rs45517382

Positions:

• chr16-2086834-A-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000548.5(TSC2):​c.4952A>G​(p.Asn1651Ser) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1651H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7 O:1
• Conservation: PhyloP100: 7.42

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 18 ACMG points.

• PM1: In a domain Rap-GAP (size 227) in uniprot entity TSC2_HUMAN there are 284 pathogenic changes around while only 47 benign (86%) in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2086833-A-C is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 16-2086834-A-G is Pathogenic according to our data. Variant chr16-2086834-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 49335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2086834-A-G is described in Lovd as [Pathogenic]. Variant chr16-2086834-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4952A>G	p.Asn1651Ser	missense_variant	38/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4952A>G	p.Asn1651Ser	missense_variant	38/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 08, 2023	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 1651 of the TSC2 protein (p.Asn1651Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with tuberous sclerosis (PMID: 9302281, 12111193, 15024740). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 49335). 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%. Experimental studies have shown that this missense change affects TSC2 function (PMID: 12906785, 14718525, 18411301, 18550814, 27078846). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PS4_Moderate+PS2+PP1+PP4+PP3_Moderate -

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 17, 2022	DNA sequence analysis of the TSC2 gene demonstrated a sequence change, c.4952A>G, in exon 38 that results in an amino acid change, p.Asn1651Ser. The p.Asn1651Ser change affects a highly conserved amino acid residue located in a domain of the TSC2 protein that is known to be functional. This sequence change has previously been described in multiple individuals with TSC2-related tuberous sclerosis complex (PMID: 9302281, 12111193, 15024740) and has not been described in population databases such as ExAC and gnomAD. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide mostly deleterious results for the p.Asn1651Ser substitution. Functional studies have demonstrated that this sequence change impacts the function of the TSC2 protein (PMID: 12906785, 18411301, 14718525, 18550814, 27078846). The p.Asn1651Ser amino acid change occurs in a region of the TSC2 gene where other missense sequence changes have been described in individuals with TSC2-related disorders including a missense change at the same position (p.Asn1651Thr, PMID: 32211034). Based on these evidences, this sequence change is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2022	Published functional studies demonstrate a damaging effect as N1651S impairs the ability of tuberin to act as a GTPase activating protein (Tee et al., 2003); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 18032745, 11741833, 11112665, 18411301, 22055460, 12906785, 1846615, 27078846, 18550814, 15798777, 14718525, 21252315, 15024740, 9302281, 11521203, 27974549, 12111193, 10205261) -

Tuberous sclerosis syndrome Pathogenic:1 Other:1

not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	Aug 09, 2016	- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2017

The p.N1651S pathogenic mutation (also known as c.4952A>G), located in coding exon 37 of the TSC2 gene, results from an A to G substitution at nucleotide position 4952. The asparagine at codon 1651 is replaced by serine, an amino acid with highly similar properties. This mutation was detected as a de novo occurrence (paternity and maternity confirmed) in an individual who fulfilled diagnostic criteria for tuberous sclerosis complex (TSC). The mutation was also detected in this individual's two sons with TSC; however, it was not identified in his third unaffected son (Maheshwar MM et al. Hum. Mol. Genet., 1997 Oct;6:1991-6). In addition, this mutation has been detected in several individuals meeting formal diagnostic criteria for TSC (Jones AC et al. Am. J. Hum. Genet., 1999 May;64:1305-15; Dabora SL et al. Am. J. Hum. Genet., 2001 Jan;68:64-80; Langkau N et al. Eur. J. Pediatr., 2002 Jul;161:393-402; Zhao XY et al. Br. J. Dermatol., 2006 Nov;155:1070-3; Kamimura T et al. Epilepsia, 2006 Jun;47:991-7). In one other study, this mutation was shown to impair the ability of tuberin to act as a GTPase enhancing protein (Tee AR et al. Curr. Biol., 2003 Aug;13:1259-68). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.4	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0030	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.87
MutPred		0.81		Gain of disorder (P = 0.0551);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.94
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.81
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.24		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45517382; hg19: chr16-2136835; COSMIC: COSV51913564; COSMIC: COSV51913564;