rs398124483
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138694.4(PKHD1):c.353del(p.Ser118IlefsTer35) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000559 in 1,610,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000058 ( 0 hom. )
Consequence
PKHD1
NM_138694.4 frameshift
NM_138694.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.407
Genes affected
PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 6-52079936-AC-A is Pathogenic according to our data. Variant chr6-52079936-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 96397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52079936-AC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.353del | p.Ser118IlefsTer35 | frameshift_variant | 5/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.353del | p.Ser118IlefsTer35 | frameshift_variant | 5/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.353del | p.Ser118IlefsTer35 | frameshift_variant | 5/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152094Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
5
AN:
152094
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000557 AC: 14AN: 251440Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135884
GnomAD3 exomes
AF:
AC:
14
AN:
251440
Hom.:
AF XY:
AC XY:
11
AN XY:
135884
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000583 AC: 85AN: 1458430Hom.: 0 Cov.: 28 AF XY: 0.0000592 AC XY: 43AN XY: 725790
GnomAD4 exome
AF:
AC:
85
AN:
1458430
Hom.:
Cov.:
28
AF XY:
AC XY:
43
AN XY:
725790
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74308
GnomAD4 genome
?
AF:
AC:
5
AN:
152094
Hom.:
Cov.:
32
AF XY:
AC XY:
3
AN XY:
74308
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:18
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 31, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Nov 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 11, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 5 of 67). (P) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (P) 0701 - Comparable variants have very strong previous evidence for pathogenicity. Many other NMD-predicted variants have previously been reported as pathogenic in patients with ARPKD (ClinVar). (P) 0801 - Strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported in multiple cases of ARPKD (ClinVar, HGMD, PMID: 15108281, PMID: 15805161, PMID: 16133180, PMID: 30650191). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 28, 2016 | The PKHD1 c.353delG (p.Ser118IlefsTer35) variant results in a frameshift and is predicted to cause a premature termination of the protein. This variant has been reported in three studies and is found in a total of four individuals with autosomal recessive polycystic kidney disease, including three compound heterozygotes and one heterozygote in whom a second variant could not be identified (Bergmann et al. 2004. Sharp et al. 2005, Losekoot et al. 2005). The p.Ser118IlefsTer35 variant was absent from 300 controls but is reported at a frequency of 0.00013 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and the potential impact of frameshift variants, the p.Ser118IlefsTer35 variant is classified as likely pathogenic for autosomal recessive polycystic kidney disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 21, 2023 | This sequence change creates a premature translational stop signal (p.Ser118Ilefs*35) 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 (rs398124483, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with autosomal recessive polycystic kidney disease (PMID: 15108281, 15805161, 16133180). ClinVar contains an entry for this variant (Variation ID: 96397). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Mar 17, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 02, 2014 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 10, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2023 | Reported with a second variant (phase unknown) in unrelated patients with polycystic kidney disease (Losekoot et al., 2005; Sharp et al., 2005; Shuster et al., 2019); Frameshift 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: 31589614, 30650191, 15108281, 15805161, 33532864, 16133180) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 25, 2019 | PVS1, PM2, PM3 - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Polycystic kidney disease 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 16, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 28, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 13, 2022 | - - |
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 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at