rs121918042

Positions:

• chr4-88046712-C-T

Variant summary

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

The NM_000297.4(PKD2):​c.1390C>T​(p.Arg464Ter) 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:7
• Conservation: PhyloP100: 3.96

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 4-88046712-C-T is Pathogenic according to our data. Variant chr4-88046712-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88046712-C-T is described in Lovd as [Pathogenic]. Variant chr4-88046712-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD2	NM_000297.4	c.1390C>T	p.Arg464Ter	stop_gained	6/15	ENST00000237596.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD2	ENST00000237596.7	c.1390C>T	p.Arg464Ter	stop_gained	6/15	1	NM_000297.4	P1
PKD2	ENST00000508588.5	c.-199+3255C>T		intron_variant		2

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

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease 2 Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1997	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 15, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 16, 2021	- -

Polycystic kidney disease Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 02, 2023	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. -

Autosomal dominant polycystic kidney disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 11, 2023

ClinVar contains an entry for this variant (Variation ID: 13521). 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. 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). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Athena Diagnostics

Oct 12, 2020

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. -

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
MutationTaster	Benign	1.0	A;A
Vest4		0.94
GERP RS		4.6

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

Publications

LitVar

Other links and lift over

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