rs398124500
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138694.4(PKHD1):c.8824C>T(p.Arg2942Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,564 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_138694.4 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 |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.8824C>T | p.Arg2942Ter | stop_gained | 57/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.8824C>T | p.Arg2942Ter | stop_gained | 57/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.8824C>T | p.Arg2942Ter | stop_gained | 57/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152034Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250982Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135610
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461530Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9AN XY: 727082
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152034Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74238
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change creates a premature translational stop signal (p.Arg2942*) in the PKHD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is present in population databases (rs398124500, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 19940839). ClinVar contains an entry for this variant (Variation ID: 96439). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 27, 2022 | Variant summary: PKHD1 c.8824C>T (p.Arg2942X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 250982 control chromosomes. c.8824C>T has been reported in the literature in individuals affected with Polycystic Kidney And Hepatic Disease. These data indicate that the variant may be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jan 16, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Nov 23, 2018 | A heterozygous nonsense variant, NM_138694.3(PKHD1):c.8824C>T, has been identified in exon 57 of 67 of the PKHD1 gene. The variant is predicted to result in a premature stop codon at position 2942 of the protein (NP_619639.3(PKHD1):p.(Arg2942*)). This variant is predicted to result in loss of protein function through nonsense mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.0007% (2 heterozygotes, 0 homozygotes). It has been previously described as pathogenic in patients with Polycystic kidney disease (ClinVar, Denamur, E et al (2010)). And many other pathogenic LoF variants in the region have also been reported (ClinVar). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 30, 2012 | - - |
Polycystic kidney disease 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 17, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at