rs766551411
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001009944.3(PKD1):c.12010C>T(p.Gln4004*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000685 in 1,460,124 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: 6.8e-7 ( 0 hom. )
Consequence
PKD1
NM_001009944.3 stop_gained
NM_001009944.3 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 6.79
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 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 16-2090802-G-A is Pathogenic according to our data. Variant chr16-2090802-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 434006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2090802-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PKD1 | NM_001009944.3 | c.12010C>T | p.Gln4004* | 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 | c.12010C>T | p.Gln4004* | stop_gained | Exon 44 of 46 | 1 | NM_001009944.3 | ENSP00000262304.4 | ||
| PKD1 | ENST00000423118.5 | c.12007C>T | p.Gln4003* | stop_gained | Exon 44 of 46 | 1 | ENSP00000399501.1 | |||
| PKD1 | ENST00000472577.1 | n.38C>T | non_coding_transcript_exon_variant | Exon 1 of 3 | 2 | |||||
| PKD1 | ENST00000564313.1 | n.531C>T | non_coding_transcript_exon_variant | Exon 3 of 3 | 4 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD3 exomes AF: 0.00000409 AC: 1AN: 244454Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133320
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460124Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 726386
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polycystic kidney disease, adult type Pathogenic:4
| Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PVS1,PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | Jul 19, 2024 | PM2_Supporting+PVS1+PS4_Moderate+PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 08, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 1 (MIM#173900). (I) 0107 - This gene is associated with autosomal dominant disease. Polycystic kidney disease 1 (MIM#173900) is predominantly caused by monoallelic variants, with rare reports of biallelic variants causing disease (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been previously reported as pathogenic, and observed in many patients with polycystic kidney disease (PKD) (Decipher). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic, and has been observed in patients with PKD (ClinVar, PMID: 29529603, pkdb.mayo.edu) (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:4
| Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2024 | 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, 16456780, 23383103, 30586318, 22508176, 31740684, 29529603, 25333066, 30413633, 35325889) - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 31, 2017 | The PKD1 c.12010C>T; p.Gln4004Ter variant (rs766551411) has been reported in two families with autosomal dominant polycystic kidney disease, and segregating with affected individuals (Audrezet 2012). An immortalized cell line carrying the variant shows reduced PKD1 incorporation in the cellular membrane, and absence in the primary cilia (Herbert 2013). This variant is reported as pathogenic in ClinVar (Variation ID: 434006), and is observed in the general population at a low overall frequency of 0.0004% (1/240348 alleles) in the Genome Aggregation Database. This variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Audrezet M et al. Autosomal dominant polycystic kidney disease: comprehensive mutation analysis of PKD1 and PKD2 in 700 unrelated patients. Hum Mutat. 2012; 33(8):1239-50. Herbert B et al. A telomerase immortalized human proximal tubule cell line with a truncation mutation (Q4004X) in polycystin-1. PLoS One. 2013; 8(1):e55191. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Jun 05, 2017 | - - |
Inborn genetic diseases Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 29, 2024 | The c.12007C>T (p.Q4003*) alteration, located in exon 44 (coding exon 44) of the PKD1 gene, consists of a C to T substitution at nucleotide position 12007. This changes the amino acid from a glutamine (Q) to a stop codon at amino acid position 4003. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of <0.001% (1/244454) total alleles studied. The highest observed frequency was 0.001% (1/108304) of European (non-Finnish) alleles. This variant was reported in multiple individuals with features consistent with polycystic kidney disease (Hoefele, 2011; Xu, 2018; Kim, 2019). Based on the available evidence, this alteration is classified as pathogenic. - |
Polycystic kidney disease Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Gln4004X variant was identified in 1 of 24 proband chromosomes from a small “discovery” cohort in a study developing NGS sequencing of ADPKD genes (Trjillano 2014). The variant was also identified in dbSNP (ID: rs766551411) and ADPKD Mutation Database (definitely pathogenic). The variant was not found in Clinvitae, COGR, MutDB, PKD1-LOVD, PKD1-LOVD 3.0, NHLBI GO, the Exome Sequencing Project and the Exome Aggregation Consortium database (August 8, 2016). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The p.Gln4004X variant leads to a premature stop codon at position 4004, 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 laboratory’s criteria to be classified as pathogenic. - |
Autosomal dominant polycystic kidney disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jun 05, 2024 | - - |
PKD1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 06, 2024 | The PKD1 c.12010C>T variant is predicted to result in premature protein termination (p.Gln4004*). This variant has been reported in individuals with autosomal dominant polycystic kidney disease (ADPKD) (see for example, Trujillano et al. 2014. PubMed ID: 25333066; Xu et al. 2018. PubMed ID: 29529603). This variant is reported in 0.00092% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense variants in PKD1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at