rs1554232224
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5
The NM_138694.4(PKHD1):c.8552T>C(p.Ile2851Thr) variant causes a missense, splice region change. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000024 ( 0 hom. )
Consequence
PKHD1
NM_138694.4 missense, splice_region
NM_138694.4 missense, splice_region
Scores
5
11
3
Splicing: ADA: 0.5304
2
Clinical Significance
Conservation
PhyloP100: 5.83
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 Uncertain_significance. Variant got 5 ACMG points.
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.961
PP5
?
Variant 6-51775810-A-G is Pathogenic according to our data. Variant chr6-51775810-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 552021.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1, Pathogenic=1}. Variant chr6-51775810-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.8552T>C | p.Ile2851Thr | missense_variant, splice_region_variant | 54/67 | ENST00000371117.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.8552T>C | p.Ile2851Thr | missense_variant, splice_region_variant | 54/67 | 1 | NM_138694.4 | P2 | |
PKHD1 | ENST00000340994.4 | c.8552T>C | p.Ile2851Thr | missense_variant, splice_region_variant | 54/61 | 5 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000241 AC: 3AN: 1244336Hom.: 0 Cov.: 18 AF XY: 0.00000159 AC XY: 1AN XY: 630670
GnomAD4 exome
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3
AN:
1244336
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Cov.:
18
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AC XY:
1
AN XY:
630670
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 09, 2023 | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2851 of the PKHD1 protein (p.Ile2851Thr). For these reasons, this variant has been classified as Pathogenic. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 552021). This missense change has been observed in individual(s) with autosomal recessive polycystic kidney disease (PMID: 15698423, 29956005, 33940108). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 19, 2017 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 30, 2022 | Variant summary: PKHD1 c.8552T>C (p.Ile2851Thr) results in a non-conservative amino acid change located in the G8 domain (IPR019316) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248318 control chromosomes. c.8552T>C has been reported in the literature as a homozygous and compound heterozygous genotype in individuals affected with Autosomal recessive polycystic kidney disease (example, Bergmann_2005, Szabo_2018, Burgmaier_2021). 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. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Polycystic kidney disease 4 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Oct 30, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;D
Vest4
MutPred
Gain of glycosylation at I2851 (P = 0.0424);Gain of glycosylation at I2851 (P = 0.0424);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at