rs1554289495
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_138694.4(PKHD1):βc.7122delβ(p.Phe2374LeufsTer41) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,590,378 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. F2374F) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_138694.4 frameshift
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.7122del | p.Phe2374LeufsTer41 | frameshift_variant | 45/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.7122del | p.Phe2374LeufsTer41 | frameshift_variant | 45/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.7122del | p.Phe2374LeufsTer41 | frameshift_variant | 45/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152094Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000139 AC: 2AN: 1438284Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1AN XY: 716952
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74306
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 24, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556905). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 19914852). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe2374Leufs*41) 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 | Counsyl | Feb 28, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 24, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 16, 2019 | Variant summary: PKHD1 c.7122delT (p.Phe2374LeufsX41) 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 was absent in 250874 control chromosomes (gnomAD). c.7122delT has been reported in the literature in individuals affected with Polycystic Kidney and Hepatic Disease (Denamur_2010, Gunay-Aygun_2010, Szabo_2018, Tong_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Polycystic kidney disease 4 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 17, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at