rs121918042
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000297.4(PKD2):c.1390C>T(p.Arg464*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,461,294 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: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
PKD2
NM_000297.4 stop_gained
NM_000297.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.96
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 4-88046712-C-T is Pathogenic according to our data. Variant chr4-88046712-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88046712-C-T is described in Lovd as [Pathogenic]. Variant chr4-88046712-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PKD2 | NM_000297.4 | c.1390C>T | p.Arg464* | stop_gained | 6/15 | ENST00000237596.7 | NP_000288.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PKD2 | ENST00000237596.7 | c.1390C>T | p.Arg464* | stop_gained | 6/15 | 1 | NM_000297.4 | ENSP00000237596.2 | ||
PKD2 | ENST00000508588.5 | c.-199+3255C>T | intron_variant | 2 | ENSP00000427131.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461294Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727006
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3
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1461294
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31
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0
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727006
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Polycystic kidney disease 2 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 1997 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 15, 2019 | The PKD2 c.1390C>T; p.Arg464Ter variant (rs121918042) has been described in multiple individuals affected with autosomal dominant polycystic kidney disease (ADPKD; see link to Mayo ADPKD database and references therein, Hoefele 2011, Viribay 1997, Xu 2018, Zhang 2018). It contains an entry in ClinVar (Variation ID: 13521) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. 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, this variant is considered pathogenic. REFERENCES Link to Mayo ADPKD database: http://pkdb.mayo.edu/cgi-bin/v2_display_mutations.cgi?GENE=PKD2&apkd_mode=PROD Hoefele J et al. Novel PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease (ADPKD). Nephrol Dial Transplant. 2011 Jul;26(7):2181-8. Viribay M et al. Novel stop and frameshifting mutations in the autosomal dominant polycystic kidney disease 2 (PKD2) gene. Hum Genet. 1997 Dec;101(2):229-34. Xu D et al. Novel Mutations in the PKD1 and PKD2 Genes of Chinese Patients with Autosomal Dominant Polycystic Kidney Disease. Kidney Blood Press Res. 2018;43(2):297-309. Zhang M et al. Identification of novel mutations and risk assessment of Han Chinese patients with autosomal dominant polycystic kidney disease. Nephrology (Carlton). 2018 Apr 6. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Dec 16, 2021 | - - |
Polycystic kidney disease Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PKD2 p.Arg464* variant was identified in 10 of 1848 proband chromosomes (frequency: 0.005) from individuals or families with ADPKD (Audrezet 2012, Chung 2006, Hateboer 2000, Hoefele 2011, Pei 1998, Torra 1999). The variant was also identified in dbSNP (ID: rs121918042) as "With Pathogenic allele", ClinVar (classified as pathogenic by OMIM), LOVD 3.0 (1x), and ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in GeneInsight-COGR or PKD1-LOVD databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Arg464* variant leads to a premature stop codon at position 464, 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 (ADPKD) 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 02, 2023 | The p.Arg464X variant in PKD2 has been reported in at least 15 individuals with polycistic kidney disease and segregated with disease in at least 6 affected individuals from 3 families (Viribay 1997 PMID: 9402976, Pei 1998 Year PMID: 9773786, Chung 2006 PMID: 17100995, Hoefele 2011 PMID: 21115670, Audrezet 2012 PMID: 22508176, Xu 2018 PMID: 29529603, Zhang 2019 PMID: 29633482, Al-Muhanna 2019 PMID: 31488014, Kim 2019 PMID: 31740684, Dong 2020 PMID: 32970388). It was absent from large population studies. This variant has also been reported in ClinVar (Variation ID 13521). This nonsense variant leads to a premature termination codon at position 464, which is predicted to lead to a truncated or absent protein. Loss of function of the PKD2 gene is an established disease mechanism in autosomal dominant polycystic kidney disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant polycystic kidney disease. ACMG/AMP Criteria applied: PVS1, PS4, PP1_Moderate, PM2_Supporting. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 12, 2020 | This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 21, 2024 | PP1_moderate, PM2, PS4, PVS1 - |
Autosomal dominant polycystic kidney disease Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 11, 2023 | ClinVar contains an entry for this variant (Variation ID: 13521). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 9402976, 29529603, 29633482, 34101167). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg464*) 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
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