6-52024589-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_138694.4(PKHD1):c.5221G>A(p.Val1741Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000366 in 1,613,994 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.5221G>A | p.Val1741Met | missense_variant | 32/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.5221G>A | p.Val1741Met | missense_variant | 32/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.5221G>A | p.Val1741Met | missense_variant | 32/61 | 5 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250908Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135754
GnomAD4 exome AF: 0.0000390 AC: 57AN: 1461798Hom.: 0 Cov.: 34 AF XY: 0.0000358 AC XY: 26AN XY: 727202
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:4Uncertain:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2002 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | research | Cavalleri Lab, Royal College of Surgeons in Ireland | Feb 05, 2020 | PS1, PM3, PP2, PP3, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1741 of the PKHD1 protein (p.Val1741Met). This variant is present in population databases (rs137852946, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of polycystic kidney disease (PMID: 11919560, 12846734, 19914852, 30773290; 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: 4111). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Polycystic kidney disease 4 Pathogenic:2Uncertain:1
Pathogenic, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Feb 14, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 27, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease; however, there are emerging reports of heterozygous carriers of PKHD1 variants developing liver cysts and nephrocalcinosis (PMID: 21945273). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant intrafamilial variability has been reported (PMID: 20301501). (I) 0200 - Variant is predicted to result in a missense amino acid change from valine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (9 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as pathogenic, likely pathogenic and as a VUS by clinical laboratories in ClinVar. This variant has also been observed in the literature as a single heterozygous variant, with other PKHD1 variants (not confirmed to be in trans), and also as homozygous in individuals with ARPKD or related phenotypes (PMIDs: 21945273, 11919560, 12846734, 19914852, 20413436, 30773290, 35372954). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 11, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 28, 2023 | Identified as a single heterozygous variant in an individual with polycystic kidney disease and in an individual with liver cysts (Ward et al., 2002; Gunay-Aygun et al., 2011); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 21945273, 11919560, 30773290, 35372954, 12846734, 34405919, 33454723) - |
See cases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Dec 21, 2021 | ACMG categories: PM1,PM2,PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at