chr4-88065479-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_000297.4(PKD2):​c.2224C>T​(p.Arg742Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000496 in 1,613,520 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PKD2
NM_000297.4 stop_gained

Scores

5
1
1

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.88
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 16 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 4-88065479-C-T is Pathogenic according to our data. Variant chr4-88065479-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 13518.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88065479-C-T is described in Lovd as [Pathogenic]. Variant chr4-88065479-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PKD2NM_000297.4 linkuse as main transcriptc.2224C>T p.Arg742Ter stop_gained 11/15 ENST00000237596.7 NP_000288.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PKD2ENST00000237596.7 linkuse as main transcriptc.2224C>T p.Arg742Ter stop_gained 11/151 NM_000297.4 ENSP00000237596 P1Q13563-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152068
Hom.:
0
Cov.:
32
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:
0.00000479
AC:
7
AN:
1461452
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727070
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152068
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74278
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
Alfa
AF:
0.0000680
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Pathogenic:4
Pathogenic, no assertion criteria providedresearchGharavi Laboratory, Columbia UniversitySep 16, 2018- -
Pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 16, 2017- -
Pathogenic, criteria provided, single submitterclinical testingAthena DiagnosticsMar 16, 2021This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with polycystic kidney disease (PKD). This variant appears to segregate with disease in at least one family, however, the available information does not rule out segregation due to chance. -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJan 17, 2024Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29633482, 30586318, 25525159, 29321346, 34101167, 18701462, 23398808, 18721488, 22832196, 21290287, 11302751, 16551655, 16223735, 30566001, 12407099, 31979107, 15130895, 10497221, 26269590, 29529603, 31740684, 12707387, 32384474, 22383692, 23300259, 25266109, 11438989, 22863349, 24658975, 37062241, 8650545) -
Autosomal dominant polycystic kidney disease Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 12, 2022Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 13518). This premature translational stop signal has been observed in individual(s) with autosomal dominant polycystic kidney disease (PMID: 8650545, 12707387, 22383692, 23300259). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918040, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Arg742*) 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). For these reasons, this variant has been classified as Pathogenic. -
Polycystic kidney disease 2 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMay 31, 1996- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.65
CADD
Pathogenic
45
DANN
Uncertain
1.0
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.98
D
MutationTaster
Benign
1.0
A;A;A
Vest4
0.99
GERP RS
5.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.27
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.27
Position offset: -24

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: rs121918040; hg19: chr4-88986631; COSMIC: COSV52937522; API