chr6-51659682-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_138694.4(PKHD1):c.10444C>T(p.Arg3482Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000235 in 1,613,826 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3482H) has been classified as Uncertain significance.
Frequency
Consequence
NM_138694.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.10444C>T | p.Arg3482Cys | missense_variant | 61/67 | ENST00000371117.8 | |
LOC124900615 | XR_926871.3 | n.155+7309G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.10444C>T | p.Arg3482Cys | missense_variant | 61/67 | 1 | NM_138694.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152116Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000519 AC: 13AN: 250682Hom.: 0 AF XY: 0.0000517 AC XY: 7AN XY: 135478
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461592Hom.: 0 Cov.: 33 AF XY: 0.0000275 AC XY: 20AN XY: 727112
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74438
ClinVar
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jan 01, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 23, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3482 of the PKHD1 protein (p.Arg3482Cys). This variant is present in population databases (rs148617572, gnomAD 0.02%). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease and related conditions (PMID: 12506140, 15108281, 15805161, 26385851, 26721323). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 188896). 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) performed at Invitae indicates that this missense variant is expected to disrupt PKHD1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Polycystic kidney disease 4 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Jul 22, 2022 | ACMG classification criteria: PS4 strong, PM2 moderated, PM3 moderated, PP1 supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense c.10444C>Tp.Arg3482Cys variant in PKHD1 gene has been reported previously in homozygous or compound heterozygous state in individuals affected with Autosomal recessive polycystic kidney disease ARPKD Quint A et al., 2016. This variant is reported with the allele frequency of 0.006% in the gnomAD Exomes and novel in 1000 Genomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic multiple submitters. The amino acid Arg at position 3482 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg3482Cys in PKHD1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. 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 indicates that this missense variant is expected to disrupt PKHD1 protein function. The variant is predicted as damaging by SIFT. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 09, 2024 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 05, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26721323, 12506140, 15108277, 15698423, 19914852, 26385851, 25114813, 15805161, 19940839, 34426522, 33940108, 15108281, 30275481, 37013475, 35812281, Corradi2022[abstract], 36964991) - |
PKHD1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 17, 2023 | The PKHD1 c.10444C>T variant is predicted to result in the amino acid substitution p.Arg3482Cys. This variant has been repeatedly reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Bergmann et al. 2003. PubMed ID: 12506140; Thakur et al. 2014. PubMed ID: 25114813; Quint et al. 2015. PubMed ID: 26721323). This variant is reported in 0.023% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-51524480-G-A). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at