16-2087910-G-C

Variant names:

• chr16-2087910-G-C
• NM_000548.5:c.5037G>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000548.5(TSC2):​c.5037G>C​(p.Glu1679Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. E1679K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.800

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 2 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.2504787).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.5037G>C	p.Glu1679Asp	missense_variant	Exon 39 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.5037G>C	p.Glu1679Asp	missense_variant	Exon 39 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Jun 21, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1679D variant (also known as c.5037G>C), located in coding exon 38 of the TSC2 gene, results from a G to C substitution at nucleotide position 5037. The glutamic acid at codon 1679 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.84	T;T;D;T;T;T;T;T;T;D;T;T;T;T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.0	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.0	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.59
Sift	Benign	0.44	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	0.55	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.0020	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.40
MutPred		0.52		Gain of sheet (P = 0.0344);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.98
ClinPred		0.15	T
GERP RS		2.1
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.44
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-2137911;