16-2085293-A-G

Variant names:

• chr16-2085293-A-G
• rs878854109
• NM_000548.5:c.4633A>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PM1 PM5 BP6 BS2

The NM_000548.5(TSC2):​c.4633A>G​(p.Ile1545Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,460,406 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I1545M) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 6.00
• Publications: 0 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: Likely_benign. The variant received -1 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 8 benign, 35 uncertain in NM_000548.5
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-2085294-T-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3342104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP6: Variant 16-2085293-A-G is Benign according to our data. Variant chr16-2085293-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 238055.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.4633A>G	p.Ile1545Val	missense_variant	Exon 36 of 42	ENST00000219476.9	NP_000539.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.4633A>G	p.Ile1545Val	missense_variant	Exon 36 of 42	5	NM_000548.5	ENSP00000219476.3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460406 Hom.: 0 Cov.: 33 AF XY: 0.00000551 AC XY: 4 AN XY: 726502

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111914

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis syndrome Uncertain:1

May 04, 2023

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 isoleucine with valine at codon 1545 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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. -

Isolated focal cortical dysplasia type II Uncertain:1

Oct 04, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.I1545V variant (also known as c.4633A>G), located in coding exon 35 of the TSC2 gene, results from an A to G substitution at nucleotide position 4633. The isoleucine at codon 1545 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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. -

Tuberous sclerosis 2 Benign:1

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.10
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Uncertain	0.64	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	1.3	L;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		6.0
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.78	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.61
Sift	Benign	0.060	T;.;.;T;.;T;.;.;T;T;.;.;.;.;T
Sift4G	Uncertain	0.030	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.89	P;.;.;.;P;P;.;.;P;P;.;.;.;.;.
Vest4		0.65
MutPred		0.53		Gain of phosphorylation at Y1549 (P = 0.1231);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.64
ClinPred		0.77	D
GERP RS		3.4
Varity_R		0.13
gMVP		0.41
Mutation Taster		=69/31	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: rs878854109; hg19: chr16-2135294;