rs774759689
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138694.4(PKHD1):c.5485C>T(p.Gln1829Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,830 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.5485C>T | p.Gln1829Ter | stop_gained | 34/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.5485C>T | p.Gln1829Ter | stop_gained | 34/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.5485C>T | p.Gln1829Ter | stop_gained | 34/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251064Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135680
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461618Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727142
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152212Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74346
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 18, 2023 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 371036). This premature translational stop signal has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 19940839, 24162162). This variant is present in population databases (rs774759689, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Gln1829*) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 27, 2021 | Variant summary: PKHD1 c.5485C>T (p.Gln1829X) 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 251064 control chromosomes. c.5485C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease (e.g. Krall_2014, Bullich_2018). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both 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 | Jun 14, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 31, 2017 | - - |
Autosomal dominant polycystic liver disease Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory of Gastroenterology and Hepatology, Radboud University Medical Center | Sep 01, 2021 | - - |
Polycystic kidney disease 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 25, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at