4-88065479-C-T
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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
NM_000297.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 5.88
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 |
---|---|---|---|---|---|---|---|---|
PKD2 | NM_000297.4 | c.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 |
---|---|---|---|---|---|---|---|---|---|---|
PKD2 | ENST00000237596.7 | c.2224C>T | p.Arg742Ter | stop_gained | 11/15 | 1 | NM_000297.4 | ENSP00000237596 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461452Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5AN XY: 727070
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74278
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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 provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 16, 2021 | This 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 submitter | clinical testing | GeneDx | Jan 17, 2024 | Nonsense 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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 12, 2022 | Algorithms 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 provided | literature only | OMIM | May 31, 1996 | - - |
Computational scores
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Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A
Vest4
GERP RS
Splicing
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Details are displayed if max score is > 0.2
DS_DG_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at