rs777999875
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_138694.4(PKHD1):c.5513A>G(p.Tyr1838Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,972 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 (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )
Consequence
PKHD1
NM_138694.4 missense
NM_138694.4 missense
Scores
7
10
2
Clinical Significance
Conservation
PhyloP100: 3.10
Genes affected
PKHD1 (HGNC:9016): (PKHD1 ciliary IPT domain containing fibrocystin/polyductin) The protein encoded by this gene is predicted to have a single transmembrane (TM)-spanning domain and multiple copies of an immunoglobulin-like plexin-transcription-factor domain. Alternative splicing results in two transcript variants encoding different isoforms. Other alternatively spliced transcripts have been described, but the full length sequences have not been determined. Several of these transcripts are predicted to encode truncated products which lack the TM and may be secreted. Mutations in this gene cause autosomal recessive polycystic kidney disease, also known as polycystic kidney and hepatic disease-1. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
?
Variant 6-52017497-T-C is Pathogenic according to our data. Variant chr6-52017497-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52017497-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.5513A>G | p.Tyr1838Cys | missense_variant | 34/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.5513A>G | p.Tyr1838Cys | missense_variant | 34/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.5513A>G | p.Tyr1838Cys | missense_variant | 34/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152202Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251246Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135762
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461652Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727148
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152320Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74484
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 23, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 28, 2023 | For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 370239). This missense change has been observed in individuals with autosomal recessive polycystic kidney disease (PMID: 15698423, 29956005). This variant is present in population databases (rs777999875, gnomAD 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1838 of the PKHD1 protein (p.Tyr1838Cys). - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 06, 2017 | - - |
Polycystic kidney disease 4 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 19, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 25, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
N;N
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Loss of sheet (P = 0.0104);Loss of sheet (P = 0.0104);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at