NM_000548.5:c.5319T>C

Variant names:

• chr16-2088505-T-C
• rs536518032
• NM_000548.5:c.5319T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000548.5(TSC2):​c.5319T>C​(p.His1773His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,612,526 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).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: TSC2 NM_000548.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.571
• 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]

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: Benign. The variant received -9 ACMG points.

• BP6: Variant 16-2088505-T-C is Benign according to our data. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084. Variant chr16-2088505-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 238084.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000591 (9/152172) while in subpopulation EAS AF = 0.00174 (9/5174). AF 95% confidence interval is 0.000907. There are 0 homozygotes in GnomAd4. There are 6 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSC2	NM_000548.5	c.5319T>C	p.His1773His	synonymous_variant	Exon 42 of 42	ENST00000219476.9	NP_000539.2
PKD1	NM_001009944.3	c.*1222A>G		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.5319T>C	p.His1773His	synonymous_variant	Exon 42 of 42	5	NM_000548.5	ENSP00000219476.3
PKD1	ENST00000262304.9	c.*1222A>G		downstream_gene_variant		1	NM_001009944.3	ENSP00000262304.4

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152054 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00174

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000600 AC: 15 AN: 250060 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000816

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1460354 Hom.: 0 Cov.: 33 AF XY: 0.0000193 AC XY: 14 AN XY: 726498

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

American (AMR) AF: 0.00 AC: 0 AN: 44718

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

East Asian (EAS) AF: 0.000680 AC: 27 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52128

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111810

Other (OTH) AF: 0.0000497 AC: 3 AN: 60366

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152172 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74402

African (AFR) AF: 0.00 AC: 0 AN: 41512

American (AMR) AF: 0.00 AC: 0 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Tuberous sclerosis 2 Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 09, 2025

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tuberous sclerosis syndrome Uncertain:1

Jul 23, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is located in the TSC2 protein. 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 been identified in 18/281426 chromosomes 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 specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 25, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:1

Sep 19, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.7
DANN	Benign	0.33
PhyloP100		-0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.32		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs536518032; hg19: chr16-2138506;