rs398124503
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138694.4(PKHD1):c.982C>T(p.Arg328Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,952 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R328R) has been classified as Likely benign. 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.982C>T | p.Arg328Ter | stop_gained | 14/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.982C>T | p.Arg328Ter | stop_gained | 14/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.982C>T | p.Arg328Ter | stop_gained | 14/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251214Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135756
GnomAD4 exome AF: 0.0000137 AC: 20AN: 1461780Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727196
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 10, 2023 | This sequence change creates a premature translational stop signal (p.Arg328*) 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 (rs398124503, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with polycystic kidney disease (PMID: 12506140, 19940839). ClinVar contains an entry for this variant (Variation ID: 96445). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 13, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 18, 2021 | Variant summary: PKHD1 c.982C>T (p.Arg328X) 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 2.8e-05 in 251214 control chromosomes. c.982C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (example, Bergmann_2003, Denamur_2010, Jung_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 | clinical testing | Counsyl | Jan 06, 2016 | - - |
Polycystic kidney disease 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 06, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Sep 06, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at