rs1554197025
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_138694.4(PKHD1):c.5342C>T(p.Thr1781Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000015 in 1,461,858 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
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
PKHD1
NM_138694.4 missense
NM_138694.4 missense
Scores
8
9
2
Clinical Significance
Conservation
PhyloP100: 4.40
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.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.935
PP5
Variant 6-52022839-G-A is Pathogenic according to our data. Variant chr6-52022839-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 552167.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr6-52022839-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKHD1 | NM_138694.4 | c.5342C>T | p.Thr1781Ile | missense_variant | 33/67 | ENST00000371117.8 | NP_619639.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKHD1 | ENST00000371117.8 | c.5342C>T | p.Thr1781Ile | missense_variant | 33/67 | 1 | NM_138694.4 | ENSP00000360158 | P2 | |
PKHD1 | ENST00000340994.4 | c.5342C>T | p.Thr1781Ile | missense_variant | 33/61 | 5 | ENSP00000341097 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13AN XY: 727238
GnomAD4 exome
AF:
AC:
22
AN:
1461858
Hom.:
Cov.:
31
AF XY:
AC XY:
13
AN XY:
727238
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 27, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2023 | Reported without a second variant in a patient with polycystic kidney disease in published literature (Furu et al., 2003); 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; This variant is associated with the following publications: (PMID: 14741187, 12874454) - |
Autosomal recessive polycystic kidney disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 24, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D;.
Eigen
Pathogenic
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
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Loss of glycosylation at T1781 (P = 0.0503);Loss of glycosylation at T1781 (P = 0.0503);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at