rs1302726543

Positions:

• chr4-88019499-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000237596.7(PKD2):​c.637C>T​(p.Arg213Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,606,664 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: 0.0000014 (0 hom.)
• Consequence: PKD2 ENST00000237596.7 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 2.42

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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-88019499-C-T is Pathogenic according to our data. Variant chr4-88019499-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 543947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88019499-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.637C>T	p.Arg213Ter	stop_gained	2/15	ENST00000237596.7	NP_000288.1
PKD2	XM_011532028.3	c.637C>T	p.Arg213Ter	stop_gained	2/14		XP_011530330.1
PKD2	NR_156488.2	n.736C>T		non_coding_transcript_exon_variant	2/14
PKD2	XM_011532029.2			upstream_gene_variant			XP_011530331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.637C>T	p.Arg213Ter	stop_gained	2/15	1	NM_000297.4	ENSP00000237596	P1
PKD2	ENST00000506727.1	n.139C>T		non_coding_transcript_exon_variant	2/4	4

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151966 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1454698 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724180

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: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151966 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74228

Gnomad4 AFR AF: 0.0000242

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	Jan 01, 2019	- -
Pathogenic, no assertion criteria provided	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2019	The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2024	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: 25333066, 27499327, 31589614, 36964972, 35372954, 22863349, 33437033, 35005812, 30586318) -

Polycystic kidney disease 2 Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 21, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 05, 2019	The PKD2 c.637C>T; p.Arg213Ter variant (rs1302726543) is reported in the literature in multiple individuals affected with autosomal dominant polycystic kidney disease (Carrera 2016, Robinson 2012, Trujillano 2014). This variant is found on a single chromosome (1/31368 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by several laboratories in ClinVar (Variation ID: 543947). 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 to be pathogenic. References: Carrera P et al. Deciphering Variability of PKD1 and PKD2 in an Italian Cohort of 643 Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD). Sci Rep. 2016 Aug 8;6:30850. Robinson C et al. Clinical utility of PKD2 mutation testing in a polycystic kidney disease cohort attending a specialist nephrology out-patient clinic. BMC Nephrol. 2012 Aug 3;13:79. Trujillano D et al. Diagnosis of autosomal dominant polycystic kidney disease using efficient PKD1 and PKD2 targeted next-generation sequencing. Mol Genet Genomic Med. 2014 Sep;2(5):412-21. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The c.637C>T(p.Arg213Ter) stop gained variant in PKD2 gene has been reported in several individuals with a personal and/or family history of autosomal dominant polycystic kidney disease (Robinson et al., 2012; Trujillano et al., 2014). This variant is reported with the allele frequency (0.003%) in the gnomad and novel in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. The nucleotide change c.637C>T in PKD2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Loss-of-function variants in PKD2 are known to be pathogenic (Robinson et al., 2012). For these reasons, this variant has been 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.Arg213* variant was identified in 9 of 1642 proband chromosomes (frequency: 0.005) from individuals or families with ADPKD (Carrera 2016, Robinson 2012, Trujillano 2014). The variant was also identified in the ClinVar database (classified as pathogenic by Invitae and one clinical laboratory), COSMIC (1x in breast tissue), and in LOVD 3.0(2x). The variant was not identified in dbSNP, ADPKD Mutation Database, ADPKD-LOVD or COGR databases. The variant was identified in control databases in 1 of 30942 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the African population in 1 of 8718 chromosomes (freq: 0.0001), but not in the European, “Other”, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Arg213* variant leads to a premature stop codon at position 213, 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

Jul 06, 2022

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 543947). This premature translational stop signal has been observed in individuals with a personal and/or family history of autosomal dominant polycystic kidney disease (PMID: 22863349, 25333066, 27499327). This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg213*) 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Benign	0.54	D
MutationTaster	Benign	1.0	A
Vest4		0.96
GERP RS		5.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1302726543; hg19: chr4-88940651; COSMIC: COSV52940052;