4-88038323-C-T

Position:

chr4-88038323-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.916C>T(p.Arg306*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000372 in 1,613,598 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: 0.0000034 ( 0 hom. )

Consequence

PKD2
NM_000297.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 4.91

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:

PKD2 (HGNC:):

PKD2 links:

Genome browser will be placed here

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 4-88038323-C-T is Pathogenic according to our data. Variant chr4-88038323-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 397507.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88038323-C-T is described in Lovd as [Pathogenic]. Variant chr4-88038323-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4 linkuse as main transcript	c.916C>T	p.Arg306*	stop_gained	4/15	ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PKD2	ENST00000237596.7 linkuse as main transcript	c.916C>T	p.Arg306*	stop_gained	4/15	1	NM_000297.4	ENSP00000237596.2	Q13563-1
PKD2	ENST00000506367.1 linkuse as main transcript	n.363C>T		non_coding_transcript_exon_variant	2/3	3
PKD2	ENST00000506727.1 linkuse as main transcript	n.502C>T		non_coding_transcript_exon_variant	4/4	4

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

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251172

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461420

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727056

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

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

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Polycystic kidney disease 2

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PM2_Supporting+PVS1+PS4 -
Pathogenic, criteria provided, single submitter	clinical testing	Center of Genomic medicine, Geneva, University Hospital of Geneva	Jul 12, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Human Genetics and Genomic Medicine, Uniklinik RWTH Aachen	Jun 17, 2021	The change is listed in the dbSNP database (dbSNP151, as of June 17, 2021) with the rs number rs200001068. In gnomAD it is reported with a frequency of 0.0003981% (1/251172) (as of June 17, 2021). The variant is mentioned as pathogenic both in ClinVar (including RCV000449565.3) and in the renowned PKD mutation database (http://pkd.mayo.edu; as of June 17, 2021). The variant has been described several times in the literature in patients with ADPKD (including AudrÃ©zet et al., 2012). In the case of stop or nonsense variants in a gene that matches the phenotype, there is also a high probability of pathogenic relevance. At this point in time, the variant is to be regarded as a "pathogenic variant" (ACMG criteria). -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Immunology and Genetics Kaiserslautern	Jan 03, 2023	ACMG Criteria: PVS1, PM2, PP5; Variant was found in heterozygous state. -
Pathogenic, criteria provided, single submitter	research	Molecular Biology Laboratory, Fundació Puigvert	Feb 01, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PP3. -

not provided

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2021	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: 25525159, 24113780, 31589614, 33532864, 29633482, 31740684, 9326320, 29529603, 33437033, 16430766, 14993477, 23300259, 32970388, 18837007, 11968093, 24374109, 10760080) -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 07, 2023	PP1, PM2_supporting, PS4_moderate, PVS1 -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 30, 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 clinical features associated with this gene. -
Pathogenic, criteria provided, single submitter	research	Gharavi Laboratory, Columbia University	Sep 16, 2018	- -

Polycystic kidney disease

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD2 p.Arg306* variant was identified in 13 of 3960 proband chromosomes (frequency: 0.003) from individuals or families with autosomal dominant polycystic kidney disease (ADPKD; Audrezet 2012, Garcia-Gonzalez 2007, Magistroni 2003, Reiterova 2002, Rossetti 2007, Rossetti 2012, Stekrova 2004, Tan 2008, Torra 2000, Veldhuisen 1997, Vouk 2006). The variant was also identified in ClinVar (classified as pathogenic by Center of Genomic Medicine Geneva and Gharavi Laboratory at Columbia University), LOVD 3.0 (3x), and ADPKD Mutation Database (as definitely pathogenic). The variant was not identified in dbSNP or PKD1-LOVD. The variant was identified in control databases in 1 of 245930 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111434 chromosomes (freq: 0.000009); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.916C>T variant leads to a premature stop codon at position 306, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PKD2 gene are an established mechanism of disease in ADPKD and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic. -

Autosomal dominant polycystic kidney disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 11, 2021

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 397507). This premature translational stop signal has been observed in individual(s) with polycystic kidney disease (PMID: 9326320, 29529603). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Arg306*) 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). -

PKD2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 13, 2024

The PKD2 c.916C>T variant is predicted to result in premature protein termination (p.Arg306*). This variant has been reported in individuals with polycystic kidney disease (see for example, Veldhuisen et al. 1997. PubMed ID: 9326320; Zhang et al. 2019. PubMed ID: 29633482; Xu et al. 2018. PubMed ID: 29529603). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Nonsense 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

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.65

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.97

Vest4

0.94

GERP RS

5.3

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.

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