6-52065051-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_138694.4(PKHD1):c.881-1G>A variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000192 in 1,563,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_138694.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.881-1G>A | splice_acceptor_variant, intron_variant | Intron 12 of 66 | 1 | NM_138694.4 | ENSP00000360158.3 | |||
PKHD1 | ENST00000340994.4 | c.881-1G>A | splice_acceptor_variant, intron_variant | Intron 12 of 60 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes AF: 0.00000696 AC: 1AN: 143682Hom.: 0 Cov.: 23
GnomAD4 exome AF: 0.00000141 AC: 2AN: 1419412Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1AN XY: 707744
GnomAD4 genome AF: 0.00000696 AC: 1AN: 143682Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 69514
ClinVar
Submissions by phenotype
Polycystic kidney disease 4 Pathogenic:3
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Autosomal recessive polycystic kidney disease Pathogenic:2
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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. 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: 499351). Disruption of this splice site has been observed in individual(s) with polycystic kidney disease (PMID: 15805161). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 12 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). -
not provided Pathogenic:2
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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: 25525159, 15805161) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at