dbSNP rs1553926929: PKD2:c.1898+5G>A (chr4-88056272-G-A) – ACMG Classification: Pathogenic (14 pts)

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_000297.4(PKD2):c.1898+5G>A variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,590,364 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PKD2
NM_000297.4 splice_region, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 8.08

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 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 4-88056272-G-A is Pathogenic according to our data. Variant chr4-88056272-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 448033.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88056272-G-A is described in Lovd as [Likely_pathogenic]. Variant chr4-88056272-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4 link	c.1898+5G>A		splice_region_variant, intron_variant	Intron 8 of 14	ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 link	c.1898+5G>A		splice_region_variant, intron_variant	Intron 8 of 14	1	NM_000297.4	ENSP00000237596.2		Q13563-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

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:

0.00000139

AC:

AN:

1438186

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

716580

show subpopulations

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:

0.00000183

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease 2

Pathogenic:2

May 24, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PKD2 c.1898+5G>A variant is reported in the literature in multiple individuals affected with autosomal dominant polycystic kidney disease (Garcia-Gonzalez 2007, Rossetti 2007, Wang 2009). This variant is reported in ClinVar (Variation ID: 448033), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by significantly weakening the nearby canonical donor splice site. Additionally, functional analyses from patient samples demonstrate aberrant transcripts predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay (Wang 2009). Based on available information, this variant is considered to be likely pathogenic. References: Garcia-Gonzalez MA et al. Evaluating the clinical utility of a molecular genetic test for polycystic kidney disease. Mol Genet Metab. 2007 Sep-Oct;92(1-2):160-7. Rossetti S et al. Comprehensive molecular diagnostics in autosomal dominant polycystic kidney disease. J Am Soc Nephrol. 2007 Jul;18(7):2143-60. Wang K et al. Evidence for pathogenicity of atypical splice mutations in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2009 Feb;4(2):442-9. -

Dec 20, 2023

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Jan 27, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

RT-PCR of leukocyte mRNA revealed splice variants all terminating with premature stop codons (Wang et al., 2009); Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and splice predictors support a deleterious effect; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19158373, 17574468, 17582161) -

Dec 29, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant appears to segregate with disease in at least one family. Assessment of experimental evidence suggests this variant results in abnormal RNA splicing. -

Polycystic kidney disease

Pathogenic:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD2 c.1898+5G>A variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with ADPKD and was not identified in 342 control chromosomes from healthy individual. The PKD2: IVS8+5G>A occurred at the 5th base pair of the splice-donor site, which is highly conserved. This variant was predicted to result in improper splicing by both the ASSA and SSPNN programs (Garcia-Gonzalez 2007). The variant was also identified in LOVD 3.0 database but no clinical information was provided; and in ADPKD Mutation Database 4X as Highly Likely Pathogenic with an amino acid frameshift prediction (p.Leu573fs) as a result of as splice defect. The variant was not identified in dbSNP, ClinVar, GeneInsight-COGR, or PKD1-LOVD, databases. Furthermore, the variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The c.1898+5G>A 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, 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing 4bp upstream at the consensus splice site location. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

Autosomal dominant polycystic kidney disease

Pathogenic:1

Jul 19, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 17574468, 17582161, 19158373). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS8+5 G>A. ClinVar contains an entry for this variant (Variation ID: 448033). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in multiple RNA products (PMID: 19158373). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 of the PKD2 gene. It does not directly change the encoded amino acid sequence of the PKD2 protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.98

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.99

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.30

Position offset: -37

DS_DL_spliceai

0.95

Position offset: -5

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