16-2088474-C-T

Variant names:

• chr16-2088474-C-T
• rs781139561
• NM_000548.5:c.5288C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000548.5(TSC2):​c.5288C>T​(p.Pro1763Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P1763R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TSC2 NM_000548.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.14
• Publications: 5 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]

PKD1 (HGNC:9008): (polycystin 1, transient receptor potential channel interacting) This gene encodes a member of the polycystin protein family. The encoded glycoprotein contains a large N-terminal extracellular region, multiple transmembrane domains and a cytoplasmic C-tail. It is an integral membrane protein that functions as a regulator of calcium permeable cation channels and intracellular calcium homoeostasis. It is also involved in cell-cell/matrix interactions and may modulate G-protein-coupled signal-transduction pathways. It plays a role in renal tubular development, and mutations in this gene cause autosomal dominant polycystic kidney disease type 1 (ADPKD1). ADPKD1 is characterized by the growth of fluid-filled cysts that replace normal renal tissue and result in end-stage renal failure. Splice variants encoding different isoforms have been noted for this gene. Also, six pseudogenes, closely linked in a known duplicated region on chromosome 16p, have been described. [provided by RefSeq, Oct 2008]

PKD1 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polycystic kidney disease 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• autosomal recessive polycystic kidney disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Caroli disease

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24638999).
• BP6: Variant 16-2088474-C-T is Benign according to our data. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935. Variant chr16-2088474-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 945935.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.5288C>T	p.Pro1763Leu	missense_variant	Exon 42 of 42	ENST00000219476.9	NP_000539.2
PKD1	NM_001009944.3	c.*1253G>A		downstream_gene_variant		ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSC2	ENST00000219476.9	c.5288C>T	p.Pro1763Leu	missense_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3
PKD1	ENST00000262304.9	c.*1253G>A		downstream_gene_variant		1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250326 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460616 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726610

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52172

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Uncertain:1 Benign:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Isolated focal cortical dysplasia type II Uncertain:1

Mar 25, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P1763L variant (also known as c.5288C>T), located in coding exon 41 of the TSC2 gene, results from a C to T substitution at nucleotide position 5288. The proline at codon 1763 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.68	D;.;.;.;.;.;.;.;.;.;.;.;T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.25	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Benign	1.9	M;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		3.1
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.9	N;.;.;N;.;N;.;.;N;N;.;.;.;.;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Sift4G	Uncertain	0.0030	D;.;.;D;.;D;.;.;D;D;.;.;.;.;D
Polyphen		0.97	D;.;.;.;B;B;.;.;B;B;.;.;.;.;.
Vest4		0.24
MutPred		0.39		Gain of loop (P = 0.0166);.;.;.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.74
ClinPred		0.38	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.093
gMVP		0.47
Mutation Taster		=85/15	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs781139561; hg19: chr16-2138475;