NM_000548.5:c.4859A>T

Variant names:

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

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>T​(p.His1620Leu) 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. 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)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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-T is Pathogenic according to our data. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-2086741-A-T is described in CliVar as Likely_pathogenic. Clinvar id is 424510.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>T	p.His1620Leu	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>T	p.His1620Leu	missense_variant	Exon 38 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 29, 2017

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A variant that is likely pathogenic has been identified in the TSC2 gene. The H1620L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The H1620L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The H1620L variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, other missense variants at the same codon (H1620Y/H1620R) and in nearby residues have been reported in association with TSC (Niida et al., 1996, Hoogeveen-Westerveld et al., 2013, 2009; Stenson et al., 2014; TSC2 LOVD), supporting the functional importance of this region of the protein. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Pathogenic	0.97	D;.;.;.;.;.;.;.;.;.;.;.;D;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.78
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	0.93	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	3.2	M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		9.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-9.7	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
REVEL	Pathogenic	0.97
Sift	Uncertain	0.0020	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0040	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		1.0	D;.;.;.;D;D;.;.;D;D;.;.;.;.;.
Vest4		0.91
MutPred		0.92		Loss of sheet (P = 0.0315);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.97
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.96
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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;