16-2086741-A-G

Variant names:

• chr16-2086741-A-G
• rs397515177
• NM_000548.5:c.4859A>G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000548.5(TSC2):​c.4859A>G​(p.His1620Arg) 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. 13/22 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. H1620Y) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:2
• Conservation: PhyloP100: 9.24
• Publications: 3 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 38 uncertain in NM_000548.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2086740-C-T is described in CliVar as Pathogenic. Clinvar id is 49327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 16-2086741-A-G is Pathogenic according to our data. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-G is described in CliVar as Likely_pathogenic. Clinvar id is 65243.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4859A>G	p.His1620Arg	missense_variant	Exon 38 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4859A>G	p.His1620Arg	missense_variant	Exon 38 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458242 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725424

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51710

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4278

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111920

Other (OTH) AF: 0.00 AC: 0 AN: 60202

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Tuberous sclerosis 2 Pathogenic:1

Feb 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 65243). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 22903760). This variant disrupts the p.His1620 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10533067, 16114042). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1620 of the TSC2 protein (p.His1620Arg). This variant is not present in population databases (gnomAD no frequency). -

Tuberous sclerosis syndrome Other:1

-

Tuberous sclerosis database (TSC2)

Significance: not provided

Review Status: no classification provided

Collection Method: curation

- -

Everolimus response Other:1

Jan 01, 2017

Division of Hematology/Oncology, Florida, Mayo Clinic

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: clinical testing

Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway, is currently approved for treatment of advanced renal-cell carcinoma (RCC) after failure of initial treatment with the tyrosine kinase inhibitors. Patients with tuberous sclerosis complex (TSC) syndrome can also develop RCC primarily mediated through mTOR signaling. However, the efficacy and duration of response of mTOR inhibition in patients with TSC-associated RCC is not well known. Herein, we describe a case of a patient with TSC2-associated metastatic RCC with mutations H1620R and Y1650C who has had an exceptional response to everolimus in the frontline setting and continues to derive benefit from mTOR inhibition 2 yr into therapy. Furthermore, the alteration H1620R in exon 37 resulting in a missense mutation is likely deleterious given our findings and previous analyses of the TSC2 gene. exceptional response

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		9.2
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.0	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0050	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.011	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.96
MutPred		0.95		Loss of sheet (P = 0.0817);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.98
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.97
gMVP		0.98
Mutation Taster		=1/99	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs397515177; hg19: chr16-2136742; COSMIC: COSV99032337;