rs1553925470

Variant names:

• chr4-88038501-CGTAA-C
• rs1553925470
• NM_000297.4:c.1094+3_1094+6delAAGT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000297.4(PKD2):​c.1094+3_1094+6delAAGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,613,684 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PKD2 NM_000297.4 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.89
• Publications: 1 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 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 4-88038501-CGTAA-C is Pathogenic according to our data. Variant chr4-88038501-CGTAA-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 434014.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000297.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	NM_000297.4	MANE Select	c.1094+3_1094+6delAAGT		splice_region intron	N/A	NP_000288.1
	PKD2	NM_001440544.1		c.1094+3_1094+6delAAGT		splice_region intron	N/A	NP_001427473.1
	PKD2	NR_156488.2		n.1193+3_1193+6delAAGT		splice_region intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.1094+3_1094+6delAAGT		splice_region intron	N/A	ENSP00000237596.2
	PKD2	ENST00000506367.1	TSL:3	n.541+3_541+6delAAGT		splice_region intron	N/A
	PKD2	ENST00000506727.1	TSL:4	n.*131_*134delGTAA		downstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 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

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461498 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727110

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44718

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111676

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74354

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41454

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Aug 12, 2024

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DNA sequence analysis of the PKD2 gene demonstrated a 4 base pair deletion in the canonical splice donor site of intron 4, c.1094+3_1094+6del. This canonical splice site deletion has been reported in several unrelated individuals with Autosomal Dominant Polycystic Kidney Disease (ADPKD) (PMID: 12707387, 30333007, 29529603). Functional analyses have demonstrated a loss of the canonical splice donor site and incorporation of intron 4 into the mRNA sequence and is expected to result in an abnormal protein product (PMID: 17582161). This sequence change has not been described in population databases such as ExAC and gnomAD. Considering the collective evidences, this canonical splice site deletion is classified as pathogenic and is the likely cause of this individual's phenotype.

Aug 18, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 09, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies detect an altered transcript retaining all or a portion of intron 4 in a patient with the variant (Rossetti et al., 2007); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 12707387, 30333007, 29529603, 18837007, 34101167, 35778421, 22383692, 17582161)

Polycystic kidney disease 2 Pathogenic:3

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.

Jan 29, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD2 c.1094+3_1094+6delAAGT variant has been described in multiple individuals and families affected with autosomal dominant polycystic kidney disease (ADPKD; see link to Mayo database, He 2018, Magistroni 2003, Rossetti 2007, Rossetti 2012). It contains an entry in ClinVar (Variation ID: 434014) and is absent from general population databases (Exome Variant Server and Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes four nucleotides of the consensus splice donor site within intron 4, and RNA studies have demonstrated a loss of the canonical splice donor site and incorporation of intron 4 into the sequence (Rossetti 2007). 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 He W et al. Novel mutations of PKD genes in Chinese patients suffering from autosomal dominant polycystic kidney disease and seeking assisted reproduction. BMC Med Genet. 2018 Oct 17;19(1):186. Magistroni R et al. Genotype-renal function correlation in type 2 autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2003 May;14(5):1164-74. 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.

May 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Pathogenic:1

Nov 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1094+3_1094+6delAAGT variant results from a deletion of 4 nucleotides between positions c.1094+3 and c.1094+6 after coding exon 4 of the PKD2 gene. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in several individuals with autosomal dominant polycystic kidney disease (Magistroni, 2003; Tan, 2009; Rossetti, 2012; He, 2018; Xu, 2018; Xu, 2021). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.

Polycystic kidney disease Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD2 c.1094+3_1094+6delAAGT variant was identified in 8 of 1056 proband chromosomes (frequency: 0.008) from individuals or families with ADPKD (Magistroni 2003, Tan 2009, Rossetti 2007, Rossetti 2012). Rosetti et al (2007) used RT-PCR analysis on lymphoblast cell lines to show that the variant abolished the normal donor site and the deletion produced a product that incorporated all or part of IVS4 into the sequence. In silico splicing models also confirm a splicing defect in a study characterizing the pathogenic potential of unclassified variants (Tan 2009). The variant was identified in the ADPKD Mutation Database (classification highly likely pathogenic), but was not identified in dbSNP, Clinvitae, ClinVar, GeneInsight COGR, PKD2-LOVD, 1000 Genomes Project, NHLBI GO Exome Sequencing Project, or in the Exome Aggregation Consortium database (March 14, 2016). The c.1094+3_1094+6delAAGT variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing, predicting the abolishment of the 5’ consensus splice site. The variant 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

Jan 07, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 12707387, 30333007, 29529603). The variant is also known as IVS4+3del4 in the literature. ClinVar contains an entry for this variant (Variation ID: 434014). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 4 of the PKD2 gene. It does not directly change the encoded amino acid sequence of the PKD2 protein, but it affects a nucleotide within the consensus splice site of the intron.

PKD2-related disorder Pathogenic:1

Jun 03, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD2 c.1094+3_1094+6delAAGT variant is predicted to result in an intronic deletion. This patient is heterozygous in the PKD2 gene for a sequence variant defined as c.1094+3_1094+6del, which is predicted to alter splicing based on available splicing prediction programs (SpliceAI, Jaganathan et al. 2019. PubMed ID: 30661751). In addition, RNA studies have shown that this variant leads to a loss of the canonical splice donor site and incorporation of intron 4 into the sequence (Figure 1C, Rossetti et al. 2007. PubMed ID: 17582161). In the literature this variant is also referred to as IVS4+3del4 or IVS4+1del4 or c.1094+1_1094+4del. This variant has been reported in individuals with autosomal dominant polycystic kidney disease (ADPKD) (Magistroni et al. 2003. PubMed ID: 12707387; Rossetti et al. 2007. PubMed ID: 17582161; Tan et al. 2009. PubMed ID: 18837007; He et al. 2018. PubMed ID: 30333007; Xu et al. 2018. PubMed ID: 29529603; Xu et al. 2021. PubMed ID: 34101167). This variant has also been reported as likely pathogenic in an ADPKD database (http://pkdb.mayo.edu). We interpret this variant as pathogenic. This finding is consistent with the diagnosis of PKD in this patient.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.94		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.94		Position offset: 0

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

Other links and lift over

dbSNP: rs1553925470; hg19: chr4-88959653;