rs45500692
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_138694.4(PKHD1):c.1736C>T(p.Thr579Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0295 in 1,613,766 control chromosomes in the GnomAD database, including 825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.024 ( 66 hom., cov: 32)
Exomes 𝑓: 0.030 ( 759 hom. )
Consequence
PKHD1
NM_138694.4 missense
NM_138694.4 missense
Scores
1
6
11
Clinical Significance
Conservation
PhyloP100: 2.73
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 Benign. Variant got -20 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0089610815).
BP6
Variant 6-52055687-G-A is Benign according to our data. Variant chr6-52055687-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 96381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-52055687-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0239 (3643/152252) while in subpopulation NFE AF= 0.0355 (2411/68002). AF 95% confidence interval is 0.0343. There are 66 homozygotes in gnomad4. There are 1726 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 66 AR gene
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0240 AC: 3647AN: 152134Hom.: 67 Cov.: 32
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GnomAD3 exomes AF: 0.0243 AC: 6097AN: 250966Hom.: 104 AF XY: 0.0244 AC XY: 3307AN XY: 135644
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GnomAD4 exome AF: 0.0300 AC: 43916AN: 1461514Hom.: 759 Cov.: 31 AF XY: 0.0295 AC XY: 21464AN XY: 727068
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GnomAD4 genome 0.0239 AC: 3643AN: 152252Hom.: 66 Cov.: 32 AF XY: 0.0232 AC XY: 1726AN XY: 74452
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TwinsUK
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125
ALSPAC
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ESP6500AA
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Asia WGS
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Benign:6
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
| Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, no assertion criteria provided | clinical testing | Natera, Inc. | May 11, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 09, 2014 | - - |
| Benign, criteria provided, single submitter | curation | SIB Swiss Institute of Bioinformatics | May 31, 2018 | This variant is interpreted as a Benign, for Polycystic kidney disease 4 with or without polycystic liver disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. - |
not specified Benign:3
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 26, 2013 | - - |
not provided Benign:2
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 12, 2020 | This variant is associated with the following publications: (PMID: 25701400) - |
| Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Polycystic kidney disease Benign:1
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKHD1 p.Thr579Met variant was identified in 8 of 1110 proband chromosomes (frequency: 0.007) from individuals or families with ADPKD and was present in 3 of 200 control chromosomes (frequency: 0.015) from healthy individuals (Sharp 2005, Losekoot 2005, Bergmann 2005, Edrees 2016, Obeidova 2015). The variant was also identified in dbSNP (ID: rs45500692) as “With Benign allele”, ClinVar (classified as benign by Invitae and Prevention Genetics), RWTH AAachen University ARPKD database (classified as polynorphism), databases. The variant was not identified in Genesight-COGR, LOVD 3.0, databases. The variant was identified in control databases in 6712 of 276722 chromosomes at a frequency of 0.024255 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Thr579 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein, in addition the variant amino acid Methionine (Met) is present in northern white cheeked gibbon, increasing the likelihood that this variant does not have clinical significance. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Polycystic kidney disease 4 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Pars Genome Lab | Jun 19, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Benign
Sift
Benign
T;T
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MPC
ClinPred
T
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