4-88074903-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.2614C>T(p.Arg872*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,922 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
Consequence
NM_000297.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152082Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251096Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135672
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461840Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727224
GnomAD4 genome 0.00000658 AC: 1AN: 152082Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74282
ClinVar
Submissions by phenotype
Polycystic kidney disease 2 Pathogenic:7
PVS1, PM2, PP3, PP4, PP5 -
Variant summary: PKD2 c.2614C>T (p.Arg872X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4e-06 in 251096 control chromosomes in gnomAD. c.2614C>T has been reported in numerous literature in individuals affected with Polycystic Kidney Disease 2 (example: Benson_2021). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, which suggests p.Arg872X PKD2 may be subject to endoplasmic reticulum-associated degradation (Liang_2008). The following publications have been ascertained in the context of this evaluation (PMID: 33454723, 18178578, 16223735). 11 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
The variant PKD2.c.2614C>T, p.(Arg872Ter), which is located in the coding exon 13 of the PKD2 gene, results from a cytosine-to-thymine substitution at nucleotide position 2614, leading to a premature stop codon at protein position 872. The premature stop codon is predicted to cause non-sense mediated decay and a truncated or absent of the gene product. Loss-of-function variants in the gene (PKD2) are known to be Pathogenic (PMID: 22863349). The variant has been reported in multiple individuals affected with autosomal dominant polycystic kidney disease. Functional studies showed an altered splicing behaviour of the altered mRNA and increased proteasomal degradation of the resulting protein (PMID: 10541293, 18178578). In addition, functional studies showed that the variant affects PKD1 binding as well as other functional deleterious consequences (PMID: 16223735, 18664456). This variant is consistently assessed as Pathogenic on 13 entries in Clinvar (Clinvar ID: 448036). This variant is classified as very rare in the overall population (one heterozygous carrier in gnomAD). The variant is classified as Pathogenic. -
This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
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) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant results in a premature termination codon (PTC) at residue 872, but also the formation of a cryptic donor site within exon 14, leading to a frameshift mutation and the formation of a downstream PTC (PMID: 10541293). This alternative protein is expected to escape nonsense-mediated decay, and also result in protein truncation. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and is regarded as one of the most common pathogenic variants in the PKD2 gene (ClinVar, pkdb.mayo.edu, PMID: 29338003). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
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not provided Pathogenic:7
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PKD2: PVS1:Strong, PM2, PS3:Moderate, PS4:Moderate, PP4 -
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Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 97 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Published functional studies demonstrate this variant results in the loss of PKD1 binding, reduction of IP3R binding and the loss of phosphorylation inhibiting cell growth (Qian et al., 1997; Li et al., 2005; Liang et al., 2008); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16223735, 19556541, 20168298, 19491093, 10497221, 25525159, 10541293, 9171830, 18664456, 11438989, 21551026, 31514750, 17574468, 18837007, 12842373, 17582161, 22508176, 33454723, 34426522, 22383692, 12707387, 24374109, 11967008) -
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Inborn genetic diseases Pathogenic:1
The c.2614C>T (p.R872*) alteration, located in exon 14 (coding exon 14) of the PKD2 gene, consists of a C to T substitution at nucleotide position 2614. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 872. 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% (1/251096) total alleles studied. The highest observed frequency was 0.001% (1/113410) of European (non-Finnish) alleles. This alteration has been reported in multiple individuals with polycystic kidney disease (Reynolds, 1999; Magistroni, 2003; Garcia-Gonzalez, 2007; Rossetti, 2007; Audrézet, 2012; Solazzo, 2018; Magistroni, 2019). This nucleotide position is not well conserved in available vertebrate species. RNA studies have demonstrated that this alteration results in abnormal splicing (Reynolds, 1999). Additionally, T lymphocytes from patients with this alteration showed a reduction of ATP-evoked calcium (Magistroni, 2019). In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice donor site. Based on the available evidence, this alteration is classified as pathogenic. -
Polycystic kidney disease Pathogenic:1
The PKD2 p.Arg872X variant was identified in 15 of 2574 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD (Tan 2008, Rossetti 2007, Magistroni 2003, Rossetti 2007, Garcia-Gonzalez 2007, Audrezet 2012). The variant was also identified in the following databases: dbSNP (ID: rs755226061), ADPKD Mutation Database (as definitely pathogenic) and in control databases in 1 of 245848 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). It was observed in the European Non-Finnish population in 1 of 111338 chromosomes (freq: 0.000009); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The variant was not identified in ClinVar, Clinvitae, COGR, LOVD 3.0, and PKD1-LOVD databases. Reverse transcription-PCR from patient lymphoblast RNA showed that the variant resulted in an out-of-frame splice variant by activating a cryptic splice site and the formation of three species of processed transcripts: a wildtype transcript, a transcript with a single base nonsense mutation, and an incorrectly spliced transcript with deletion which leads to a consequent frame shift resulting in a stop codon eight residues downstream of the splice junction; there was no exon skipping found (Reynolds 1999). In 1 proband, the variant also co-occurred with a highly pathogenic PKD1 variant (G2814R) (Garcia-Gonzalez 2007). The c.2614C>T variant leads to a premature stop codon at position 872 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 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
This sequence change creates a premature translational stop signal (p.Arg872*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 22508176). ClinVar contains an entry for this variant (Variation ID: 448036). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at