4-88074903-C-T

Position:

• chr4-88074903-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PP3_Moderate PP5_Very_Strong

The NM_000297.4(PKD2):​c.2614C>T​(p.Arg872Ter) 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:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: PKD2 NM_000297.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:17
• Conservation: PhyloP100: 1.55

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]

ACMG classification

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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-88074903-C-T is Pathogenic according to our data. Variant chr4-88074903-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 448036.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88074903-C-T is described in Lovd as [Pathogenic]. Variant chr4-88074903-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.2614C>T	p.Arg872Ter	stop_gained	14/15	ENST00000237596.7	NP_000288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.2614C>T	p.Arg872Ter	stop_gained	14/15	1	NM_000297.4	ENSP00000237596	P1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251096 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135672

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152082 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74282

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease 2 Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Diagnostics Centre, Carl Von Ossietzky University Oldenburg	Sep 08, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	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 -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 24, 2022	- -
Pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Feb 05, 2020	PVS1, PM2, PP3, PP4, PP5 -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Feb 17, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 04, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 26, 2023	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. -

not provided Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	PKD2: PVS1, PS3:Moderate, PS4:Moderate, PP1, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 15, 2016	- -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Mar 27, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 07, 2022	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2024

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; Audr&eacute;zet, 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

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 29, 2023

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.74
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.87	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.98
GERP RS		4.2

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.85		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs755226061; hg19: chr4-88996055;