chr4-88046712-C-T

Variant names:

• chr4-88046712-C-T
• rs121918042
• NM_000297.4:c.1390C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 3.96
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polycystic kidney disease 2

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Pathogenic. The variant received 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 VariationId is 13521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4	c.1390C>T	p.Arg464*	stop_gained	Exon 6 of 15	ENST00000237596.7	NP_000288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7	c.1390C>T	p.Arg464*	stop_gained	Exon 6 of 15	1	NM_000297.4	ENSP00000237596.2
PKD2	ENST00000508588.5	c.-199+3255C>T		intron_variant	Intron 1 of 9	2		ENSP00000427131.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461294 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727006

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111484

Other (OTH) AF: 0.00 AC: 0 AN: 60380

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000653 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease 2 Pathogenic:5

Nov 05, 2024

Gharavi Laboratory, Columbia University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: case-control

- -

Dec 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 15, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 07, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PKD2 c.1390C>T (p.Arg464X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251326 control chromosomes (gnomAD). c.1390C>T has been reported in the literature in individuals affected with Polycystic Kidney Disease 2 (e.g. Viribay_1997). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 9402976). ClinVar contains an entry for this variant (Variation ID: 13521). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:3

Oct 12, 2020

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jun 21, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PP1_moderate, PM2, PS4, PVS1 -

Aug 05, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 22508176, 25266109, 9402976, 29529603, 9773786, 10760080, 21115670, 31488014, 29633482, 31740684, 34101167, 36938073, 36186434, 34732400, 32970388, 17100995) -

Polycystic kidney disease Pathogenic:2

Feb 02, 2023

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Autosomal dominant polycystic kidney disease Pathogenic:1

Feb 11, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. ClinVar contains an entry for this variant (Variation ID: 13521). 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.96	D
PhyloP100		4.0
Vest4		0.94
GERP RS		4.6
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121918042; hg19: chr4-88967864; COSMIC: COSV52939698; COSMIC: COSV52939698;