rs1555444985

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001009944.3(PKD1):c.12031C>T(p.Gln4011*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,460,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PKD1
NM_001009944.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 4.84

Publications

3 publications found

Variant links:

Genes affected

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

PKD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-2090781-G-A is Pathogenic according to our data. Variant chr16-2090781-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 447961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD1	NM_001009944.3 link	c.12031C>T	p.Gln4011*	stop_gained	Exon 44 of 46	ENST00000262304.9	NP_001009944.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD1	ENST00000262304.9 link	c.12031C>T	p.Gln4011*	stop_gained	Exon 44 of 46	1	NM_001009944.3	ENSP00000262304.4		P98161-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460256

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51908

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111934

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease, adult type

Pathogenic:5

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PVS1+PS2_Supporting+PS4_Supporting+PP4 -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 16, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG criteria used: PVS1, PS4, PP1, PP4_Strong -

Jul 01, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: PKD1 c.12031C>T (p.Gln4011X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 245558 control chromosomes. c.12031C>T has been observed in individual(s) affected with Polycystic Kidney Disease 1 (example: Shuster_2019). The following publication has been ascertained in the context of this evaluation (PMID: 30650191). ClinVar contains an entry for this variant (Variation ID: 447961). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided

Pathogenic:2

Jul 26, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12220456, 9521593, 30650191, 33639313, 10729710, 10923038, 22508176, 35783601, 34032358, 25333066, 22383692) -

Oct 21, 2016

Athena Diagnostics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Polycystic kidney disease

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PKD1 p.Gln4011* variant was identified in 6 of 2598 proband chromosomes (frequency: 0.002) from individuals or families with autosomal dominant polycystic kidney disease and was not identified in 518 control chromosomes from healthy individuals (Hwang 2016, Rossetti 2012, Eo 2002, Bogdanova 2000, AudrâˆšÂ©zet 2012, Daniells 1998, Kim 2000, Stekrova 2009). The variant was also identified in ClinVar (classified as pathogenic by Athena Diagnostics and Fulgent Genetics) and in the ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in LOVD 3.0 or the PKD1-LOVD databases. It was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Gln4011* variant leads to a premature stop codon at position 4011, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD1 gene are an established mechanism of disease in autosomal dominant polycystic kidney disease and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Renal cyst

Pathogenic:1

Sep 13, 2019

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Benign

0.73

PhyloP100

4.8

Vest4

0.84

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over