rs557405366
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_138694.4(PKHD1):c.10858C>T(p.Arg3620Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,613,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3620H) has been classified as Likely benign.
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152090Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 250934Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135614
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461534Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727080
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152090Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74264
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Uncertain:2
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This sequence change replaces arginine with cysteine at codon 3620 of the PKHD1 protein (p.Arg3620Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with PKHD1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
See cases Uncertain:1
ACMG categories: PM2,PP3 -
not provided Uncertain:1
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at