4-88065496-G-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000297.4(PKD2):​c.2240+1G>C variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,392 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: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PKD2
NM_000297.4 splice_donor, intron

Scores

5
1
1
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 9.64
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-88065496-G-C is Pathogenic according to our data. Variant chr4-88065496-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 872745.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
PKD2NM_000297.4 linkc.2240+1G>C splice_donor_variant, intron_variant Intron 11 of 14 ENST00000237596.7 NP_000288.1 Q13563-1Q9UEU6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKD2ENST00000237596.7 linkc.2240+1G>C splice_donor_variant, intron_variant Intron 11 of 14 1 NM_000297.4 ENSP00000237596.2 Q13563-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461392
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727046
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

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.2240+1G>C variant was identified in the literature in 1 of 440 proband chromosomes (freq: 0.002) from individuals or families with ADPKD (Hwang 2016) for which it was classified as pathogenic. This variant was not identified in dbSNP, Clinvitae, ClinVar, GeneInsight-COGR, the ADPKD Mutation Database, PKD2-LOVD, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project and the Exome Aggregation Consortium database (August 8, 2016). In the ADPKD database and PKD2 (LOVD) databases alternate substitutions at the c.2240+1 position are classified as pathogenic. The c.2240+1G>C variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the abolishment of the 5’ splice site. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Polycystic kidney disease 2 Pathogenic:1
Jan 20, 2025
Department of Human Genetics, Hannover Medical School
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

PVS1, PM2_Supporting, PM5, PP3 -

not provided Pathogenic:1
Nov 01, 2019
CeGaT Center for Human Genetics Tuebingen
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.42
CADD
Pathogenic
35
DANN
Uncertain
1.0
Eigen
Pathogenic
1.3
Eigen_PC
Pathogenic
1.2
FATHMM_MKL
Pathogenic
1.0
D
GERP RS
6.0

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.72
Position offset: -41
DS_DL_spliceai
0.99
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.

Other links and lift over

dbSNP: rs1553927783; hg19: chr4-88986648; API