rs1057516577
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138694.4(PKHD1):c.9718C>T(p.Arg3240Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,638 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.9718C>T | p.Arg3240Ter | stop_gained | 58/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.9718C>T | p.Arg3240Ter | stop_gained | 58/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.9718C>T | p.Arg3240Ter | stop_gained | 58/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251230Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135760
GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461638Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5AN XY: 727142
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 27, 2021 | Variant summary: PKHD1 c.9718C>T (p.Arg3240X) 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 8e-06 in 251230 control chromosomes (gnomAD). c.9718C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney and Hepatic Disease (Bergmann_2003, Bergmann_2005, Shuster_2019, Burgmaier_2021). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change creates a premature translational stop signal (p.Arg3240*) 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 (no rsID available, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 12506140, 30650191). ClinVar contains an entry for this variant (Variation ID: 370548). 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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 26, 2016 | - - |
Polycystic kidney disease 4 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 18, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The stop-gained variant c.9718C>T(p.Arg3240Ter) in the PKHD1 gene has been reported in the compound heterozygous state in multiple individuals affected with polycystic kidney disease (Bergmann et al., 2003; Bergmann et al., 2005). The variant has 0.0007% allele frequency in gnomAD Exomes. It has been submitted to ClinVar as Pathogenic/ Likely Pathogenic. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants has been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. In the absence of another reportable variant, the molecular diagnosis is not confirmed. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 21, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at