GeneBe

4-88007930-AC-ACC

Variant names:

Variant summary

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

The NM_000297.4(PKD2):​c.203dupC​(p.Ala69GlyfsTer23) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,446,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

PKD2
NM_000297.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: -0.393
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
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 4-88007930-A-AC is Pathogenic according to our data. Variant chr4-88007930-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 477627.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.203dupC p.Ala69GlyfsTer23 frameshift_variant Exon 1 of 15 ENST00000237596.7 NP_000288.1 Q13563-1Q9UEU6
PKD2XM_011532028.3 linkc.203dupC p.Ala69GlyfsTer23 frameshift_variant Exon 1 of 14 XP_011530330.1
PKD2NR_156488.2 linkn.302dupC non_coding_transcript_exon_variant Exon 1 of 14

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PKD2ENST00000237596.7 linkc.203dupC p.Ala69GlyfsTer23 frameshift_variant Exon 1 of 15 1 NM_000297.4 ENSP00000237596.2 Q13563-1
ENSG00000286618ENST00000662475.1 linkn.112+435dupG intron_variant Intron 1 of 2

Frequencies

GnomAD3 genomes
AF:
0.0000133
AC:
2
AN:
150278
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000132
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
GnomAD4 exome
AF:
7.72e-7
AC:
1
AN:
1295888
Hom.:
0
Cov.:
33
AF XY:
0.00000157
AC XY:
1
AN XY:
636938
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000347
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:
0.0000133
AC:
2
AN:
150278
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
73376
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000132
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:
0.00000756

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Polycystic kidney disease 2 Pathogenic:4
Feb 24, 2025
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: PKD2 c.203dupC (p.Ala69GlyfsX23) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.203dupC has been reported in the literature in multiple individuals affected with Polycystic Kidney Disease 2 (e.g. Cornec-Le Gall_2017). These data indicate that the variant is very likely to be associated with disease. The following publication has been ascertained in the context of this evaluation (PMID: 28356211). ClinVar contains an entry for this variant (Variation ID: 477627). Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 01, 1999
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Jan 24, 2022
MGZ Medical Genetics Center
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 20, 2024
Fulgent Genetics, Fulgent Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Pathogenic:3
Feb 08, 2022
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Frameshift 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22508176, 10411676, 14993477, 18837007, 29633482, 33437033, 34101167) -

Jan 21, 2021
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In some published literature, this variant is referred to as 198insC. This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. -

Sep 16, 2018
Gharavi Laboratory, Columbia University
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

Autosomal dominant polycystic kidney disease Pathogenic:2
Jan 01, 2019
Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Nov 20, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ala69Glyfs*23) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with autosomal dominant polycystic kidney disease (PMID: 10411676, 18837007, 22508176). This variant is also known as 198insC. ClinVar contains an entry for this variant (Variation ID: 477627). For these reasons, this variant has been classified as Pathogenic. -

Inborn genetic diseases Pathogenic:1
Oct 08, 2024
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.203dupC (p.A69Gfs*23) alteration, located in exon 1 (coding exon 1) of the PKD2 gene, consists of a duplication of C at position 203, causing a translational frameshift with a predicted alternate stop codon after 23 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant, also referred to as 198insC, was reported in multiple individuals with features consistent with PKD2-related polycystic kidney disease (Torra, 1999; Audrézet, 2012). Based on the available evidence, this alteration is classified as pathogenic. -

PKD2-related disorder Pathogenic:1
Jul 15, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The PKD2 c.203dupC variant is predicted to result in a frameshift and premature protein termination (p.Ala69Glyfs*23). This variant was reported in individuals with polycystic kidney disease (see for example, Zhang et al. 2018. PubMed ID: 29633482; Groopman et al. 2019. PubMed ID: 30586318, Table S7). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in PKD2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs1187336837; hg19: chr4-88929082; API