rs1334913120
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_138694.4(PKHD1):c.5909-2delA variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000687 in 1,454,818 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
PKHD1
NM_138694.4 splice_acceptor, intron
NM_138694.4 splice_acceptor, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.99
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.017341513 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.4, offset of 27, new splice context is: gctgattttcatggccccAGgac. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-51934323-CT-C is Pathogenic according to our data. Variant chr6-51934323-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551218.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.5909-2delA | splice_acceptor_variant, intron_variant | ENST00000371117.8 | NP_619639.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.5909-2delA | splice_acceptor_variant, intron_variant | 1 | NM_138694.4 | ENSP00000360158.3 | ||||
PKHD1 | ENST00000340994.4 | c.5909-2delA | splice_acceptor_variant, intron_variant | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1454818Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 724096
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GnomAD4 genome Cov.: 33
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33
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2023 | This sequence change affects a splice site in intron 36 of the PKHD1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKHD1 are known to be pathogenic (PMID: 19940839). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 25114813). ClinVar contains an entry for this variant (Variation ID: 551218). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 24, 2017 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 26, 2023 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25114813) - |
PKHD1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 11, 2023 | The PKHD1 c.5909-2delA variant is predicted to result in a deletion affecting a canonical splice site. This variant has been reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (Thakur et al. 2014. PubMed ID: 25114813). To our knowledge, this variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant has been interpreted as likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/551218/). This variant is interpreted as pathogenic. - |
Polycystic kidney disease 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 15, 2024 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -9
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at