rs1131692280

Positions:

chr4-88043458-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong

The NM_000297.4(PKD2):c.1319+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000251 in 1,591,652 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PKD2
NM_000297.4 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 9.96

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:

PKD2 (HGNC:):

PKD2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07705539 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-88043458-G-A is Pathogenic according to our data. Variant chr4-88043458-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 430967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88043458-G-A is described in Lovd as [Pathogenic]. Variant chr4-88043458-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4 linkuse as main transcript	c.1319+1G>A		splice_donor_variant, intron_variant		ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 linkuse as main transcript	c.1319+1G>A		splice_donor_variant, intron_variant		1	NM_000297.4	ENSP00000237596.2		Q13563-1
PKD2	ENST00000508588.5 linkuse as main transcript	c.-199+1G>A		splice_donor_variant, intron_variant		2		ENSP00000427131.1		B4DFN3

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

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

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250634

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135442

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1439456

Hom.:

Cov.:

AF XY:

0.00000279

AC XY:

AN XY:

717472

show subpopulations

Gnomad4 AFR exome

AF:

0.0000606

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000482

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:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease 2

Pathogenic:5

Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Aug 07, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 27, 2019	The PKD2 c.1319+1G>A variant (rs1131692280), also known as IVS5+1G>A, is reported in the literature in multiple individuals and families affected with autosomal dominant polycystic kidney disease (ADPKD) (Magistroni 2003, Rossetti 2012, Tan 2009, Torra 2000). This variant is found on only three chromosomes (3/282036 alleles) in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 430967). This variant abolishes the canonical splice donor site of intron 5, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: 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. 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. Novel method for genomic analysis of PKD1 and PKD2 mutations in autosomal dominant polycystic kidney disease. Hum Mutat. 2009 Feb;30(2):264-73. Torra R et al. Increased prevalence of polycystic kidney disease type 2 among elderly polycystic patients. Am J Kidney Dis. 2000 Oct;36(4):728-34. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Apr 21, 2022	PVS1 PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics Department, Catlab	Aug 07, 2024	The c.1319+1G>A variant in the PKD2 gene modifies the canonical donor splicing site of intron 5 and is expected to alter the protein function (PVS1). It has been previously found in multiple patients with autosomal dominant policystic kidney disease (PMID: 12707387, 11007674, 18837007) (PS4_Moderate) and it has been shown to segregate in one of our affected families (PP1). The variant has a very low frequency in the gnomAD database 4.1 (AF= 2.5e-06) (PM2). Additionally, the variant is classified as pathogenic in the ADPKD database. With all the available evidence, the variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 04, 2024	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 30, 2020	This variant is expected to severely impact normal RNA splicing, and consequently, protein structure and/or function. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in at least one individual with clinical features associated with this gene. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2024	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 29790872, 12707387, 18837007, 22383692, 35314260, 27499327, 36938073, 11007674) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 11, 2023

The c.1319+1G>A intronic variant results from a G to A substitution one nucleotide(s) after coding exon 5 of the PKD2 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNAdecay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown; however, and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the A allele has an overall frequency of 0.001% (3/282036) total alleles studied. The highest observed frequency was 0.012% (3/24960) of African alleles. This mutation has been reported in multiple individuals with a clinical diagnosis of polycystic kidney disease (Torra, 2000; Rossetti, 2012). In one individual with polycystic kidney disease, this mutation was identified in conjunction with a missense variant in PKD1 (Magistroni, 2003). This nucleotide position is highly conserved in available vertebrate species. 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

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD2 c.1319+1G>A variant was identified in 9 of 1178 proband chromosomes (frequency: 0.008) from individuals or families with ADPKD (Hwang 2016, Magistroni 2003, Rossetti 2012, Tan 2008, Torra 2000). The variant was also identified in dbSNP (ID: rs1131692280) with â€šÃ„ÃºPathogenic alleleâ€šÃ„Ã¹, in ClinVar (classified pathogenic by Invitae, Ambry Genetics and Hudson Alpha Institute for Biotechnology), LOVD 3.0 (2x), and the ADPKD Mutation Database (classified as definitely pathogenic). The variant was not identified in the PKD1-LOVD database. The variant was identified in 3 of 276406 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 3 of 24026 chromosomes (freq: 0.0001); it was not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.1319+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information 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 20, 2019

For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PKD2 are known to be pathogenic (PMID: 17582161, 22863349). Disruption of this splice site has been reported in families affected with polycystic kidney disease (PMID: 11007674, 12707387, 22383692). It is also known as IVS5+1G>A in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 5 of the PKD2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

GERP RS

4.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.98

Position offset: -1

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