rs1208166840

Positions:

• chr16-2080165-G-A
• chr16-2080165-G-C
• chr16-2080165-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000548.5(TSC2):​c.3398G>A​(p.Gly1133Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000137 in 1,460,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G1133R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense, splice_region
• Scores: Splicing: ADA: 0.9673
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.3398G>A	p.Gly1133Glu	missense_variant, splice_region_variant	30/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.3398G>A	p.Gly1133Glu	missense_variant, splice_region_variant	30/42	5	NM_000548.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460554 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726560

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2017

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TSC2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 1133 of the TSC2 protein (p.Gly1133Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.57
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	0.74	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Uncertain	2.4	M;.;.;.;.;.;.;.;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.6	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0020	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0060	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.84
MutPred		0.23		Gain of solvent accessibility (P = 0.024);.;Gain of solvent accessibility (P = 0.024);.;.;.;.;Gain of solvent accessibility (P = 0.024);.;Gain of solvent accessibility (P = 0.024);.;.;.;.;.;
MVP		0.96
ClinPred		0.98	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.68
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.030		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: rs1208166840; hg19: chr16-2130166; COSMIC: COSV104587069; COSMIC: COSV104587069;