rs766551411
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
Consequence
NM_001009944.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
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 Cov.: 34
GnomAD3 exomes AF: 0.00000409 AC: 1AN: 244454Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133320
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460124Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 726386
GnomAD4 genome Cov.: 34
ClinVar
Submissions by phenotype
Polycystic kidney disease, adult type Pathogenic:4
PVS1,PS4 -
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 -
PM2_Supporting+PVS1+PS4_Moderate+PP4 -
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not provided Pathogenic:4
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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) -
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. -
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Inborn genetic diseases Pathogenic:1
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
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
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PKD1-related disorder Pathogenic:1
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at