rs1555454411
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001009944.3(PKD1):c.6487C>T(p.Arg2163Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 1,415,434 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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD1 | NM_001009944.3 | c.6487C>T | p.Arg2163Ter | stop_gained | 15/46 | ENST00000262304.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD1 | ENST00000262304.9 | c.6487C>T | p.Arg2163Ter | stop_gained | 15/46 | 1 | NM_001009944.3 | P5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000141 AC: 2AN: 1415434Hom.: 0 Cov.: 34 AF XY: 0.00000286 AC XY: 2AN XY: 700218
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Polycystic kidney disease, adult type Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Feb 23, 2023 | The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic (ClinVar ID: VCV000433972 / PMID: 11115377). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 11, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 06, 2021 | - - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 29, 2022 | 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: 30586318, 25525159, 11967008, 11115377, 31317121, 30816285, 22508176, 19515475, 31488014, 33168999) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 22, 2021 | This variant is expected to result in the loss of a functional protein. This variant was not reported in large, multi-ethnic, general populations (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 22, 2017 | - - |
Autosomal dominant polycystic kidney disease Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD1 p.Arg2163X variant was identified in 4 of 1662 proband chromosomes (frequency: 0.002) from British and French individuals or families with ADPKD, segregating with the disease (Rossetti 2001, Audrézet 2012). The variant was identified in ADPKD Mutation Database with classification definitely pathogenic; and was not identified in dbSNP, Clinvitae, ClinVar, GeneInsight COGR, MutDB, ADPKD Mutation Database (classification), PKD1-LOVD, and PKD1-LOVD 3.0, 1000 Genomes Project, NHLBI GO Exome Sequencing Project, or the Exome Aggregation Consortium database (March 14, 2016). The p.Arg2163X variant leads to a premature stop codon at position 2163, 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. - |
Renal cyst Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at