4-88038380-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000297.4(PKD2):c.973C>T(p.Arg325Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000434 in 1,613,930 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: 0.0000034 ( 0 hom. )
Consequence
PKD2
NM_000297.4 stop_gained
NM_000297.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 4.24
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 16 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
?
Variant 4-88038380-C-T is Pathogenic according to our data. Variant chr4-88038380-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 411870.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88038380-C-T is described in Lovd as [Pathogenic]. Variant chr4-88038380-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PKD2 | NM_000297.4 | c.973C>T | p.Arg325Ter | stop_gained | 4/15 | ENST00000237596.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PKD2 | ENST00000237596.7 | c.973C>T | p.Arg325Ter | stop_gained | 4/15 | 1 | NM_000297.4 | P1 | |
PKD2 | ENST00000506367.1 | n.420C>T | non_coding_transcript_exon_variant | 2/3 | 3 | ||||
PKD2 | ENST00000506727.1 | downstream_gene_variant | 4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251098Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135674
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polycystic kidney disease 2 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Feb 02, 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 (3 heterozygotes). (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: 28356211, PMID: 34101167). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 04, 2018 | The PKD2 c.973C>T; p.Arg325Ter variant is reported in the literature in multiple individuals affected with polycystic kidney disease (Oka 2014, Raj 2017, Rossetti 2007, Yu 2011). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 411870), and is found in the general population with an overall allele frequency of 0.001% (3/245,840 alleles) in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Arg325Ter variant is considered to be pathogenic. References: Oka M et al. A novel mutation of the PKD2 gene in a Japanese patient with autosomal dominant polycystic kidney disease and complete situs inversus. Am J Kidney Dis. 2014 64(4):660. Raj S et al. Mutational screening of PKD2 gene in the north Indian polycystic kidney disease patients revealed 28 genetic variations. J Genet. 2017 Dec;96(6):885-893. Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 18(7):2143-60. Yu C et al. Identification of novel mutations in Chinese Hans with autosomal dominant polycystic kidney disease. BMC Med Genet. 2011 12:164. - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | PKD2 NM_000297.3 exon 4 p.Arg325* (c.973C>T): This variant has been reported in the literature in 5 individuals with polycystic kidney disease (Rossetti 2007 PMID:17582161, Oka 2014 PMID:25149526, Raj 2017 PMID:29321346, Yu 2011 PMID:22185115). This variant is present in 0.002% (1/34548) of Latino alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/4-88959532-C-T). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar, with multiple labs classifying this variant as pathogenic (Variation ID:411870). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Wu 2009 PMID: 10655152). In summary, this variant is classified as pathogenic based on the data above (reported probands, impact to protein etc.) - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 23, 2021 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 11, 2022 | This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2023 | 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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22508176, 17582161, 25149526, 29321346, 30333007, 33569422, 34733539, 22185115, 33437033, 34101167) - |
Autosomal dominant polycystic kidney disease Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 411870). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 17582161, 22185115, 25149526). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg325*) 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). - |
Pathogenic, criteria provided, single submitter | research | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 03, 2023 | The c.973C>T (p.R325*) alteration, located in exon 4 (coding exon 4) of the PKD2 gene, consists of a C to T substitution at nucleotide position 973. This changes the amino acid from a arginine (R) to a stop codon at amino acid position 325. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the T allele has an overall frequency of 0.001% (3/251098) total alleles studied. The highest observed frequency was 0.016% (1/6126) of Other alleles. This mutation has been reported in multiple individuals with polycystic kidney disease (Raj, 2017; Cornec-Le Gall, 2017; He, 2018; Xu, 2021; Mallawaarachchi, 2021). Based on the available evidence, this alteration is classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A
Vest4
GERP RS
Splicing
Name
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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