16-2072341-T-C

Position:

• chr16-2072341-T-C

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.2198T>C​(p.Leu733Pro) 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. 12/20 in silico tools predict a damaging 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. L733V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 7.95

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 chr16-2072340-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 16-2072341-T-C is Pathogenic according to our data. Variant chr16-2072341-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 50119.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2072341-T-C is described in Lovd as [Pathogenic]. Variant chr16-2072341-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TSC2	NM_000548.5	c.2198T>C	p.Leu733Pro	missense_variant	20/42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.2198T>C	p.Leu733Pro	missense_variant	20/42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 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	Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	Jul 19, 2022	According to ACMG GL 2015, this variant located in Hamartin binding domain (PM1), absent from controls (PM2), assumed de novo (PM6), multiple lines of computational evidence support a deleterious effect (PP3). Detected in the patient with clinically definitive tuberous sclerosis complex (PP4) and also reported as pathogenic/likely pathogenic in LOVD database (PP5). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 22, 2024	Criteria applied: PS4_MOD,PM2,PP3,PP4 -

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	0.99
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.94	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.1	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.9	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0020	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.98
MutPred		0.97		Gain of catalytic residue at L733 (P = 0.0187);Gain of catalytic residue at L733 (P = 0.0187);Gain of catalytic residue at L733 (P = 0.0187);.;Gain of catalytic residue at L733 (P = 0.0187);Gain of catalytic residue at L733 (P = 0.0187);Gain of catalytic residue at L733 (P = 0.0187);Gain of catalytic residue at L733 (P = 0.0187);.;Gain of catalytic residue at L733 (P = 0.0187);Gain of catalytic residue at L733 (P = 0.0187);Gain of catalytic residue at L733 (P = 0.0187);Gain of catalytic residue at L733 (P = 0.0187);Gain of catalytic residue at L733 (P = 0.0187);.;
MVP		0.99
ClinPred		1.0	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs45517217; hg19: chr16-2122342;