chr4-88074822-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000297.4(PKD2):c.2533C>T(p.Arg845*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,613,878 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PKD2
NM_000297.4 stop_gained
NM_000297.4 stop_gained
Scores
3
3
1
Clinical Significance
Conservation
PhyloP100: 2.44
Genes affected
PKD2 (HGNC:9009): (polycystin 2, transient receptor potential cation channel) This gene encodes a member of the polycystin protein family. The encoded protein is a multi-pass membrane protein that functions as a calcium permeable cation channel, and is involved in calcium transport and calcium signaling in renal epithelial cells. This protein interacts with polycystin 1, and they may be partners in a common signaling cascade involved in tubular morphogenesis. Mutations in this gene are associated with autosomal dominant polycystic kidney disease type 2. [provided by RefSeq, Mar 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-88074822-C-T is Pathogenic according to our data. Variant chr4-88074822-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 523770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88074822-C-T is described in Lovd as [Pathogenic]. Variant chr4-88074822-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251174Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135728
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461732Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727172
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GnomAD4 genome 0.0000131 AC: 2AN: 152146Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polycystic kidney disease 2 Pathogenic:4
| Pathogenic, criteria provided, single submitter | research | Molecular Biology Laboratory, Fundació Puigvert | Feb 01, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2+PS4_Moderate+PP1_Strong+PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 25, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Mar 31, 2022 | 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 2 (MIM#613095). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (2 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times in individuals with ADPKD (ClinVar, PMID: 22863349, 24658975). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2022 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 33532864, 24658975, 30369598, 27782177, 22863349, 11007674, 22008521, 22383692, 11438989, 22508176) - |
Polycystic kidney disease Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD2 p.Arg845* variant was identified in 11 of 458 proband chromosomes (frequency: 0.02) from individuals or families with Autosomal Dominant Polycystic Kidney Disease (Virzi 2014, Robinson 2012, Magistroni 2003). The variant was also identified in dbSNP (ID: rs369678636) as “NA”, ClinVar (classified as pathogenic by GeneDx and Gharavi Laboratory, Columbia University), and in ADPKD Mutation Database (as definitely pathogenic). The variant was identified in control databases in 3 of 245930 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 2 of 33574 chromosomes (freq: 0.00006), European in 1 of 111414 chromosomes (freq: 0.000009), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, Other, and South Asian populations. The variant was not identified in PKD2-LOVD. The variant was reported as a possible founder mutation in the Italian population by Virzi 2014. The c.2533C>T variant leads to a premature stop codon at position 845, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD2 gene are an established mechanism of disease in autosomal dominant polycystic kidney disease and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Autosomal dominant polycystic kidney disease Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 27, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 523770). This premature translational stop signal has been observed in individual(s) with clinical features of polycystic kidney disease (PMID: 11007674, 24658975). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs369678636, gnomAD 0.006%). This sequence change creates a premature translational stop signal (p.Arg845*) in the PKD2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). - |
PKD2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 15, 2024 | The PKD2 c.2533C>T variant is predicted to result in premature protein termination (p.Arg845*). This variant has been reported to be pathogenic for autosomal dominant polycystic kidney disease (ADPKD) (Torra et al. 2000. PubMed ID: 11007674; Virzì et al. 2014. PubMed ID: 24658975). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in PKD2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
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