16-2057163-A-G

Variant names:

• chr16-2057163-A-G
• rs397515266
• NM_000548.5:c.833A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM1 BP4_Strong BP6 BS2

The NM_000548.5(TSC2):​c.833A>G​(p.His278Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000129 in 1,399,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H278P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 5.46
• 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: Benign. The variant received -7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 45 uncertain in NM_000548.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.06334984).
• BP6: Variant 16-2057163-A-G is Benign according to our data. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094. Variant chr16-2057163-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238094.
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.833A>G	p.His278Arg	missense_variant	Exon 9 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.833A>G	p.His278Arg	missense_variant	Exon 9 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000129 AC: 18 AN: 1399466 Hom.: 0 Cov.: 32 AF XY: 0.0000130 AC XY: 9 AN XY: 690268

African (AFR) AF: 0.00 AC: 0 AN: 31602

American (AMR) AF: 0.00 AC: 0 AN: 35718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.00 AC: 0 AN: 79266

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49220

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5686

European-Non Finnish (NFE) AF: 0.0000167 AC: 18 AN: 1079030

Other (OTH) AF: 0.00 AC: 0 AN: 58020

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Nov 29, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Feb 25, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Tuberous sclerosis 2 Benign:2

Dec 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Uncertain:1

Aug 30, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces histidine with arginine at codon 278 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided Benign:1

Sep 06, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	0.0022	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Benign	0.71
DEOGEN2	Benign	0.32	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.69
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.72	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.063	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.9	N;.;.;.;N;N;.;.;.;N;.;N;.;.;.
PhyloP100		5.5
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.0	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.42
Sift	Benign	1.0	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Benign	1.0	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Polyphen		0.0	B;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.24
MutPred		0.47		Loss of catalytic residue at H278 (P = 0.1025);Loss of catalytic residue at H278 (P = 0.1025);Loss of catalytic residue at H278 (P = 0.1025);.;Loss of catalytic residue at H278 (P = 0.1025);Loss of catalytic residue at H278 (P = 0.1025);Loss of catalytic residue at H278 (P = 0.1025);Loss of catalytic residue at H278 (P = 0.1025);.;Loss of catalytic residue at H278 (P = 0.1025);Loss of catalytic residue at H278 (P = 0.1025);Loss of catalytic residue at H278 (P = 0.1025);Loss of catalytic residue at H278 (P = 0.1025);Loss of catalytic residue at H278 (P = 0.1025);.;
MVP		0.66
ClinPred		0.043	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.26
Mutation Taster		=42/58	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: rs397515266; hg19: chr16-2107164;