rs45517118

chr16-2056242-G-Achr16-2056242-G-Cchr16-2056242-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.646G>A(p.Glu216Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,916 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E216Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense, splice_region
• Scores: Splicing: ADA: 0.7808
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8 O:1
• Conservation: PhyloP100: 8.40

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: MetaRNN computational evidence supports a deleterious effect, 0.774

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TSC2	NM_000548.5	c.646G>A	p.Glu216Lys	missense_variant, splice_region_variant	7/42	ENST00000219476.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TSC2	ENST00000219476.9	c.646G>A	p.Glu216Lys	missense_variant, splice_region_variant	7/42	5	NM_000548.5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461688 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727142

Gnomad4 AFR exome AF: 0.0000299

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74372

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 24, 2023	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. Experimental studies have shown that this missense change does not substantially affect TSC2 function (PMID: 21309039). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 49379). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 216 of the TSC2 protein (p.Glu216Lys). -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Tuberous sclerosis syndrome Uncertain:2 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 03, 2021	- -
not provided, no classification provided	curation	Tuberous sclerosis database (TSC2)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 02, 2023	- -

Lymphangiomyomatosis;C1846385:Isolated focal cortical dysplasia type II;C1860707:Tuberous sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 27, 2021

- -

Isolated focal cortical dysplasia type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 25, 2023

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2019

The c.646G>A (p.E216K) alteration is located in exon 7 (coding exon 6) of the TSC2 gene. This alteration results from a G to A substitution at nucleotide position 646, causing the glutamic acid (E) at amino acid position 216 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Benign	1.9	L;.;.;.;L;L;.;.;.;L;.;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.3	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.62
Sift	Benign	0.48	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Uncertain	0.020	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.99	D;.;.;.;D;D;.;.;D;P;.;.;.;.;.
Vest4		0.85
MutPred		0.44		Gain of ubiquitination at E216 (P = 0.0185);Gain of ubiquitination at E216 (P = 0.0185);Gain of ubiquitination at E216 (P = 0.0185);.;Gain of ubiquitination at E216 (P = 0.0185);Gain of ubiquitination at E216 (P = 0.0185);Gain of ubiquitination at E216 (P = 0.0185);Gain of ubiquitination at E216 (P = 0.0185);.;Gain of ubiquitination at E216 (P = 0.0185);Gain of ubiquitination at E216 (P = 0.0185);Gain of ubiquitination at E216 (P = 0.0185);Gain of ubiquitination at E216 (P = 0.0185);Gain of ubiquitination at E216 (P = 0.0185);.;
MVP		0.82
ClinPred		0.94	D
GERP RS		5.0
Varity_R		0.42
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.78
dbscSNV1_RF	Pathogenic	0.79
SpliceAI score (max)		0.010		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: rs45517118; hg19: chr16-2106243;