6-51903601-A-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_138694.4(PKHD1):c.6992T>A(p.Ile2331Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000457 in 1,610,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00046 ( 0 hom. )
Consequence
PKHD1
NM_138694.4 missense
NM_138694.4 missense
Scores
3
7
9
Clinical Significance
Conservation
PhyloP100: 3.71
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 Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-51903601-A-T is Pathogenic according to our data. Variant chr6-51903601-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-51903601-A-T is described in Lovd as [Pathogenic]. Variant chr6-51903601-A-T is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.12714306). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PKHD1 | NM_138694.4 | c.6992T>A | p.Ile2331Lys | missense_variant | 43/67 | ENST00000371117.8 | NP_619639.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PKHD1 | ENST00000371117.8 | c.6992T>A | p.Ile2331Lys | missense_variant | 43/67 | 1 | NM_138694.4 | ENSP00000360158.3 | ||
| PKHD1 | ENST00000340994.4 | c.6992T>A | p.Ile2331Lys | missense_variant | 43/61 | 5 | ENSP00000341097.4 |
Frequencies
GnomAD3 genomes 0.000408 AC: 62AN: 152028Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000458 AC: 115AN: 251278Hom.: 0 AF XY: 0.000457 AC XY: 62AN XY: 135806
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GnomAD4 exome AF: 0.000462 AC: 674AN: 1458008Hom.: 0 Cov.: 29 AF XY: 0.000469 AC XY: 340AN XY: 725472
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GnomAD4 genome 0.000408 AC: 62AN: 152028Hom.: 0 Cov.: 32 AF XY: 0.000471 AC XY: 35AN XY: 74268
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:20
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Autosomal recessive polycystic kidney disease Pathogenic:7
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 06, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The PKHD1 c.6992T>A (p.Ile2331Lys) missense variant has been reported in four studies in which it is found in a total of 11 patients with autosomal recessive polycystic kidney disease, all in a compound heterozygous state, at least three of whom carried a frameshift variant on the second allele (Ward et al. 2002; Bergmann et al. 2005; Sharp et al. 2005; Gunay-Aygun et al. 2010). Segregation with disease has been shown in at least two studies (Ward et al. 2002; Bergmann et al. 2005). The p.Ile2331Lys variant was absent from 500 controls and is reported at a frequency of 0.00287 in the European (Finnish) population in the Exome Aggregation Consortium. Based on the collective evidence, the p.Ile2331Lys variant is classified as pathogenic for autosomal recessive polycystic disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
| Likely pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change replaces isoleucine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2331 of the PKHD1 protein (p.Ile2331Lys). This variant is present in population databases (rs200179145, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with polycystic kidney disease (PMID: 11919560, 12506140, 15698423, 15805161, 19914852, 26673778). 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: 188813). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PKHD1 protein function. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 20, 2020 | Variant summary: PKHD1 c.6992T>A (p.Ile2331Lys) results in a non-conservative amino acid change located in the Right handed beta helix domain (IPR039448) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 251478 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PKHD1 causing Polycystic Kidney and Hepatic Disease (0.00046 vs 0.0071), allowing no conclusion about variant significance. c.6992T>A has been reported in the literature in multiple compound heterozygous individuals affected with Polycystic Kidney and Hepatic Disease (Ward_2002, Bergmann_2003, Bergmann_2005). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 31, 2017 | - - |
Polycystic kidney disease 4 Pathogenic:7
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 06, 2021 | PM1, PM2, PP2, PP3, PP5 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 04, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with polycystic kidney disease 4, with or without hepatic disease (MIM#263200). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. There is significant intrafamilial variation of severity (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from isoleucine to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (134 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2, v3) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated right handed beta helix (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as likely pathogenic and pathogenic, and reported in compound heterozygous individuals with milder renal disease and autosomal recessive polycystic kidney disease (ClinVar, PMID: 33532864, PMID: 15698423). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate in four affected pairs of siblings (PMID: 15698423). (SP) 1205 - This variant has been shown to be maternally inherited. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 30, 2022 | PM3_Strong, PM1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Aug 21, 2023 | Criteria applied: PM3_VSTR,PM1,PM2_SUP - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 27, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Blueprint Genetics | Mar 02, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 12846734, 15805161, 12874454, 29956005, 14741187, 20413436, 16523049, 19914852, 15698423, 11919560, 15108277, 12506140, 15706593, 26673778, 29935118, 31980526, 27535533, 31589614) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | PKHD1: PM3:Very Strong, PM1, PM2, BP4 - |
Polycystic kidney disease Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKHD1 p.Ile2331Lys variant was identified in 15 of 836 proband chromosomes (frequency: 0.018) from individuals or families with ARPKD, and was not identified in 200 control chromosomes from healthy individuals (Adeva 2006, Bergmann 2005, Furu 2004, Gunay-Aygun 2010, Sharp 2005). The variant was also identified in dbSNP (ID: rs200179145) as “With likely pathogenic allele”, Clinvitae database (likely pathogenic by ClinVar), the ClinVar database (likely pathogenic by Counsyl), RWTH AAachen University ARPKD database (pathogenic) and PKHD1-LOVD. This variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 40 of 121394 chromosomes (freq. 0.0003) in the following populations: European in 21 of 66734 chromosomes (freq. 0.0003), Finish in 19 of 6614 chromosomes (freq. 0.003) and not identified in African, East Asian, Latino, South Asian or Other population. The p.Ile2331 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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 the case study by Adeva (2006) the variant was identified with a truncating mutation in an infant with respiratory distress and hyperechogenic liver and kidneys with intrahepatic bile duct dilatation, the variant was classified as definitely pathogenic. Two ARPKD studies classified the variant as pathogenic (Sharp 2005) and probably pathogenic (Gunay-Aygun 2010) by in silico and segregation analysis. In addition, Bergmann (2005) and Furu (2004) suggest the variant in combination with truncating mutation has a rather moderate effect and associated with minor renal disease. 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 pathogenic role for this variant. This variant is classified as likely pathogenic. - |
PKHD1-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 23, 2024 | The PKHD1 c.6992T>A variant is predicted to result in the amino acid substitution p.Ile2331Lys. This variant has been repeatedly reported to be pathogenic for autosomal recessive polycystic kidney disease (ARPKD) (see for example, Ward et al. 2002. PubMed ID: 11919560; Bergmann et al. 2003. PubMed ID: 12506140). This variant is reported in 0.31% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MVP
MPC
ClinPred
T
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gMVP
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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