rs776060304
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5
The NM_138694.4(PKHD1):c.6900C>T(p.Asn2300=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,610,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000040 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
PKHD1
NM_138694.4 synonymous
NM_138694.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.653
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
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Variant 6-51903693-G-A is Pathogenic according to our data. Variant chr6-51903693-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 558073.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2, Pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.6900C>T | p.Asn2300= | synonymous_variant | 43/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.6900C>T | p.Asn2300= | synonymous_variant | 43/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.6900C>T | p.Asn2300= | synonymous_variant | 43/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000395 AC: 6AN: 151890Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251312Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135818
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1458548Hom.: 0 Cov.: 29 AF XY: 0.0000207 AC XY: 15AN XY: 725802
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:4Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 01, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 27, 2022 | Variant summary: PKHD1 c.6900C>T alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Two predict the variant strengthens a cryptic 3' acceptor site. One study reported the variant resulted in the skipping of 47 nucleotides of exon 43 resulting in a reading frame shift (Balci_2017), while a second study reported that while this alternate splicing of exon 43 occurs at a basal level in control cells, it is promoted by the synonymous change shifting the expression ratio in favour of a shorter, out-of-frame transcript (Molinari_2020). The variant allele was found at a frequency of 1.6e-05 in 251312 control chromosomes. c.6900C>T has been reported in the literature in multiple individuals affected with Polycystic Kidney And Hepatic Disease in the compound heterozygous and homozygous state (Balci_2017, Molinari_2020, Burgmaier_2021). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One submitter classified the variant as likely pathogenic while two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 19, 2023 | This sequence change affects codon 2300 of the PKHD1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PKHD1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs776060304, gnomAD 0.004%). This variant has been observed in individual(s) with polycystic kidney disease (PMID: 15698423, 15805161, 28170084; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 558073). Studies have shown that this variant results in aberrant mRNA splicing and introduces a premature termination codon (PMID: 28170084). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
PKHD1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 08, 2024 | The PKHD1 c.6900C>T variant is not predicted to result in an amino acid change (p.=). This variant has been reported in the homozygous and compound heterozygous state in individuals with PKHD1-related disease (Balci et al. 2017. PubMed ID: 28170084; Table S3, Burgmaier et al. 2021. PubMed ID: 33940108). The c.6900C site has been reported to be an exonic splicing enhancer and the C to T change caused aberrant mRNA splicing (a 47-nucleotide loss), resulting in a frameshift and premature protein termination (Balci et al. 2017. PubMed ID: 28170084; Molinari et al. 2020. PubMed ID: 33059616). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic. - |
Polycystic kidney disease 4 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 20, 2024 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2020 | Published functional studies suggest a negative effect on the gene product (Balci et al., 2017); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 33059616, 28170084, 15805161, 15698423) - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 34
Find out detailed SpliceAI scores and Pangolin per-transcript scores at