rs1553925453

Positions:

chr4-88038371-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000237596.7(PKD2):c.964C>T(p.Arg322Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000248 in 1,613,858 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R322Q) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PKD2
ENST00000237596.7 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 4.94

Variant links:

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]

PKD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000237596.7

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr4-88038372-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 802079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.996

PP5

Variant 4-88038371-C-T is Pathogenic according to our data. Variant chr4-88038371-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88038371-C-T is described in Lovd as [Pathogenic]. Variant chr4-88038371-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4 linkuse as main transcript	c.964C>T	p.Arg322Trp	missense_variant	4/15	ENST00000237596.7	NP_000288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 linkuse as main transcript	c.964C>T	p.Arg322Trp	missense_variant	4/15	1	NM_000297.4	ENSP00000237596	P1	Q13563-1
PKD2	ENST00000506367.1 linkuse as main transcript	n.411C>T		non_coding_transcript_exon_variant	2/3	3
PKD2	ENST00000506727.1 linkuse as main transcript	n.550C>T		non_coding_transcript_exon_variant	4/4	4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00000205

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000187

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152160

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74334

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2023	Reported to segregate with disease in multiple affected individuals from a single family in published literature (Reiterova et al., 2002); however, limited information was provided on the family; Published functional studies suggest this variant disrupts normal complex formation (Gainullin et al., 2015); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16767665, 25574838, 15192819, 11968093, 17100995, 23300259, 28356211, 17582161, 32332171, 33454723, 33437033, 34101167, 32816041, 35778421, 37028763) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 14, 2023	PP1, PP3, PM2, PM5, PS3_moderate, PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2022	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. Assessment of experimental evidence suggests this variant results in abnormal protein function. (25574838, 32332171) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 19, 2022	DNA sequence analysis of the PKD2 gene demonstrated a sequence change, c.964C>T, in exon 4 that results in an amino acid change, p.Arg322Trp. The p.Arg322Trp change affects a highly conserved amino acid residue located in the polycystin cation channel protein domain of the PKD2 protein that is known to be functional. The p.Arg322Trp substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change segregated with disease in six individuals from a family with autosomal dominant polycystic kidney disease (PMID: 11968093) and has also been observed in several other unrelated individuals affected with polycystic kidney disease (PMID: 15192819, 17100995, 17582161, 23300259, 28356211). Additionally, other sequence changes impacting the same amino acid residue (p.ARg322Gly, p.Arg322Gln) have been identified in individuals with polycystic kidney disease (PMID: 26139440, 15772804). This sequence change has not been described in population databases such as ExAC and gnomAD. Collectively, these evidences indicate this sequence change is pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	Jan 01, 2019	- -

Polycystic kidney disease 2

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 26, 2019	The PKD2 c.964C>T; p.Arg322Trp variant is reported in several unrelated individuals with ADKPD (Chung 2006, Cornec-Le Gall 2017, Neumann 2013, Rossetti 2007) and shown to co-segregate with disease in a family (Reiterova 2002). This variant is classified as likely pathogenic/pathogenic in ClinVar (Variation ID: 448039). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The arginine at codon 322 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Furthermore, other variants at this codon (Arg322Gln, Arg322Gly, Arg322Pro) have been associated with ADPKD (Audrezet 2016, Jin 2016, Neumann 2013, Robinson 2012, Rossetti 2012, Tan 2011, Trujillano 2014, Woerner 2006), suggesting this residue is critical for proper protein function. Based on available information, the p.Arg322Trp variant is considered to be pathogenic. REFERENCES Audrezet MP et al. Comprehensive PKD1 and PKD2 Mutation Analysis in Prenatal Autosomal Dominant Polycystic Kidney Disease. J Am Soc Nephrol. 2016 Mar;27(3):722-9. Chung W et al. PKD2 gene mutation analysis in Korean autosomal dominant polycystic kidney disease patients using two-dimensional gene scanning. Clin Genet. 2006 Dec;70(6):502-8. Cornec-Le Gall E et al. PKD2-Related Autosomal Dominant Polycystic Kidney Disease: Prevalence, Clinical Presentation, Mutation Spectrum, and Prognosis. Am J Kidney Dis. 2017 Oct;70(4):476-485. Jin M et al. System analysis of gene mutations and clinical phenotype in Chinese patients with autosomal-dominant polycystic kidney disease. Sci Rep. 2016 Oct 26;6:35945. Neumann HP et al. Epidemiology of autosomal-dominant polycystic kidney disease: an in-depth clinical study for south-western Germany. Nephrol Dial Transplant. 2013 Jun;28(6):1472-87. Reiterova J et al. Four novel mutations of the PKD2 gene in Czech families with autosomal dominant polycystic kidney disease. Hum Mutat. 2002 May;19(5):573. 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 Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60. Rossetti S et al. Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol. 2012 May;23(5):915-33. Tan YC et al. Aberrant PKD2 splicing due to a presumed novel missense mutation in autosomal-dominant polycystic kidney disease. Clin Genet. 2011 Sep;80(3):287-92. 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. Woerner AC et al. Tuberous sclerosis complex and polycystic kidney disease together: an exception to the contiguous gene syndrome. Genet Med. 2006 Mar;8(3):197-8. -
Likely pathogenic, criteria provided, single submitter	research	Cavalleri Lab, Royal College of Surgeons in Ireland	Feb 05, 2020	PM2, PM2, PP2, PP3, PP4, PP5 -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2022

The c.964C>T (p.R322W) alteration is located in exon 4 (coding exon 4) of the PKD2 gene. This alteration results from a C to T substitution at nucleotide position 964, causing the arginine (R) at amino acid position 322 to be replaced by a tryptophan (W). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been observed in multiple individuals with a personal and/or family history of autosomal dominant polycystic kidney disease (Reiterová, 2002; Zhang, 2005; Rossetti, 2007; Neumann, 2013; Cornec-Le Gall, 2017; Benson, 2021; Mallawaarachchi, 2021; Kim, 2021; Yu, 2022). This amino acid position is highly conserved in available vertebrate species. Functional studies indicate this variant impairs channel gating without impacting channel cilia localization (Vien, 2020). This alteration is predicted to be deleterious by in silico analysis. 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.Arg322Trp variant was identified in 1 of 28 proband chromosomes (frequency: 0.04) from individuals or families with ADPKD of Czech ethnicity and was not identified in 100 control chromosomes from healthy individuals (Reiterova 2002,). The variant was also identified in the LOVD 3.0 database but no relevant information was given. The variant was not identified in dbSNP, ClinVar, ADPKD Mutation and PKD1-LOVD, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Exome Aggregation Consortium (August 8th 2016) nor the Genome Aggregation Consortium (Feb 27, 2017) control databases. The variant p.Arg322Trp in exon 4 causes a change from a positively charged arginine to a hydrophobic tryptophan in the first extracellular loop of the polycystin 2. In one study, this substitution segregated with the disease in a large family with six affected individuals. 50 unrelated individuals were tested and no similar change was observed (Reiterova 2002). The variant was also identified in a Chinese family with ADPKD (Zhang 2004). A different variant at the same position, where arginine is replaced with glutamine, was identified as disease causing and segregated with four individuals with ADPKD and one affected obligate carrier (Woerner 2006). In a letter to the editor, it is stated that a disease causing missense mutation p.Arg322Trp has been reported among PKD2- linked families of both Czech and Chinese ethnicities. The arginine at codon 322 of the PKD2 gene on chromosome 4q21-23 is remarkably conserved across species, indicating its importance this position. Indeed, as Reiterova et al. point out, this mutation variant occurs in a large extracellular loop of polycystin 2, and is likely to be necessary for proper folding of the protein, as well as interaction with other molecules (Reiterova 2002Woerner 2006). The p.Arg322 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the tryptophanTrp variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Polycystin cation channel of PKD2 Polycystic kidney disease type 2 protein functional domains increasing the likelihood that it may have clinical significance. In summary, this variant meets our laboratoryâ€šÃ„Ã´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

Nov 08, 2022

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg322 amino acid residue in PKD2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15772804, 16540757, 23300259, 25574838). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects PKD2 function (PMID: 25574838). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PKD2 protein function. ClinVar contains an entry for this variant (Variation ID: 448039). This missense change has been observed in individuals with autosomal dominant polycystic kidney disease (PMID: 11968093, 15192819, 23300259; 17582161.¬†17100995). It has also been observed to segregate with disease in related individuals. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 322 of the PKD2 protein (p.Arg322Trp). -

PKD2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2024

The PKD2 c.964C>T variant is predicted to result in the amino acid substitution p.Arg322Trp. This variant has been reported to segregate with autosomal dominant polycystic kidney disease (ADPKD) in a large Czech family (Reiterova et al. 2002. PubMed ID: 11968093). This variant has also been reported in several other unrelated patients with ADPKD (Chung et al. 2006. PubMed ID: 17100995; P15 in Kim et al. 2021. PubMed ID: 32816041; Supp. Table 3 in Benson et al. 2021. PubMed ID: 33454723). Different changes at the same codon have also been reported in ADPKD patients (p.Arg322Gly, Audrézet et al. 2016. PubMed ID: 26139440; p.Arg322Gln, Robinson et al. 2012. PubMed ID: 22863349 and Trujillano et al. 2014. PubMed ID: 25333066). This variant has not been reported in gnomAD, indicating this variant is rare. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.63

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0090

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.94

MutPred

0.96

Loss of disorder (P = 0.0646);

MVP

0.96

MPC

0.66

ClinPred

1.0

GERP RS

2.8

Varity_R

0.81

gMVP

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over