16-2071818-G-C

Variant names:

• chr16-2071818-G-C
• rs137854168
• NM_000548.5:c.1981G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000548.5(TSC2):​c.1981G>C​(p.Gly661Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,152 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G661V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3 O:1
• Conservation: PhyloP100: 5.31
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• tuberous sclerosis

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• tuberous sclerosis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics
• lymphangioleiomyomatosis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• tuberous sclerosis complex

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.1981G>C	p.Gly661Arg	missense_variant	Exon 19 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.1981G>C	p.Gly661Arg	missense_variant	Exon 19 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.90e-7 AC: 1 AN: 1449152 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719786

African (AFR) AF: 0.00 AC: 0 AN: 33204

American (AMR) AF: 0.00 AC: 0 AN: 43616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25800

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39164

South Asian (SAS) AF: 0.00 AC: 0 AN: 84156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5336

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1106906

Other (OTH) AF: 0.00 AC: 0 AN: 59814

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1

Oct 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 661 of the TSC2 protein (p.Gly661Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 22903760). ClinVar contains an entry for this variant (Variation ID: 49697). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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 does not substantially affect TSC2 function (PMID: 22903760). 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. -

not provided Uncertain:1

Apr 12, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: variant does not significantly disrupt the function of the TSC1-TSC2 complex (Hoogeveen-Westerveld 2013); This variant is associated with the following publications: (PMID: 22903760) -

Hereditary cancer-predisposing syndrome Uncertain:1

Jan 14, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G661R variant (also known as c.1981G>C), located in coding exon 18 of the TSC2 gene, results from a G to C substitution at nucleotide position 1981. The glycine at codon 661 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Tuberous sclerosis syndrome Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Benign	0.10
Eigen_PC	Benign	-0.043
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.22	D
MetaRNN	Uncertain	0.73	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M;M;.;.;.;M;.;M;.;.;.
PhyloP100		5.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.2	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Uncertain	0.62
Sift	Uncertain	0.0050	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Pathogenic	0.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.98	D;.;.;.;P;P;.;.;P;D;.;.;.;.;.
Vest4		0.58
MutPred		0.41		Loss of glycosylation at S660 (P = 0.0638);Loss of glycosylation at S660 (P = 0.0638);Loss of glycosylation at S660 (P = 0.0638);.;Loss of glycosylation at S660 (P = 0.0638);Loss of glycosylation at S660 (P = 0.0638);Loss of glycosylation at S660 (P = 0.0638);Loss of glycosylation at S660 (P = 0.0638);.;Loss of glycosylation at S660 (P = 0.0638);Loss of glycosylation at S660 (P = 0.0638);Loss of glycosylation at S660 (P = 0.0638);Loss of glycosylation at S660 (P = 0.0638);Loss of glycosylation at S660 (P = 0.0638);.;
MVP		0.95
ClinPred		0.92	D
GERP RS		2.4
Varity_R		0.21
gMVP		0.59
Mutation Taster		=74/26	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs137854168; hg19: chr16-2121819;