4-88008021-CGAGGAG-CGAGGAGGAG

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000297.4(PKD2):c.305_307dupAGG(p.Glu102dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.00112 in 1,516,764 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0046 ( 9 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 2 hom. )

Consequence

PKD2
NM_000297.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.02

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:

ENSG00000286618 (HGNC:):

ENSG00000286618 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP6

Variant 4-88008021-C-CGAG is Benign according to our data. Variant chr4-88008021-C-CGAG is described in ClinVar as [Likely_benign]. Clinvar id is 193079.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00463 (698/150616) while in subpopulation AFR AF= 0.0148 (611/41376). AF 95% confidence interval is 0.0138. There are 9 homozygotes in gnomad4. There are 351 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 698 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PKD2	NM_000297.4 link	c.305_307dupAGG	p.Glu102dup	disruptive_inframe_insertion	Exon 1 of 15	ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6
PKD2	XM_011532028.3 link	c.305_307dupAGG	p.Glu102dup	disruptive_inframe_insertion	Exon 1 of 14		XP_011530330.1
PKD2	NR_156488.2 link	n.404_406dupAGG		non_coding_transcript_exon_variant	Exon 1 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 link	c.305_307dupAGG	p.Glu102dup	disruptive_inframe_insertion	Exon 1 of 15	1	NM_000297.4	ENSP00000237596.2		Q13563-1
ENSG00000286618	ENST00000662475.1 link	n.112+342_112+344dupCTC		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00462

AC:

696

AN:

150526

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00324

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00955

Gnomad NFE

AF:

0.000341

Gnomad OTH

AF:

0.00580

GnomAD3 exomes

AF:

0.00146

AC:

143

AN:

97700

Hom.:

AF XY:

0.00105

AC XY:

AN XY:

53432

show subpopulations

Gnomad AFR exome

AF:

0.0198

Gnomad AMR exome

AF:

0.00174

Gnomad ASJ exome

AF:

0.000149

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000178

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000608

Gnomad OTH exome

AF:

0.00366

GnomAD4 exome

AF:

0.000729

AC:

996

AN:

1366148

Hom.:

Cov.:

AF XY:

0.000642

AC XY:

433

AN XY:

673950

show subpopulations

Gnomad4 AFR exome

AF:

0.0161

Gnomad4 AMR exome

AF:

0.00203

Gnomad4 ASJ exome

AF:

0.0000405

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000117

Gnomad4 FIN exome

AF:

0.0000297

Gnomad4 NFE exome

AF:

0.000248

Gnomad4 OTH exome

AF:

0.00226

GnomAD4 genome

AF:

0.00463

AC:

698

AN:

150616

Hom.:

Cov.:

AF XY:

0.00477

AC XY:

351

AN XY:

73562

show subpopulations

Gnomad4 AFR

AF:

0.0148

Gnomad4 AMR

AF:

0.00323

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000341

Gnomad4 OTH

AF:

0.00574

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Jul 15, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 09, 2017

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 26, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:3

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PKD2 p.Glu102dup variant was identified in 2 of 1564 proband chromosomes (frequency: 0.001) from French, British, and North America individuals or families with ADPKD (Audrezet 2012, Garcia-Gonzalez 2007). There is conflicting evidence in the literature and databases. The variant was identified in a 54 year old male patient with bilateral multicystic kidneys and situs inverus, the duplication segregating with the disease (cystic kidneys) in 1 of the probandâ€šÃ„Ã´s children and was absent in the 3 unaffected children suggesting that the variant is disease causing (Bataille 2011). The variant was identified in dbSNP (ID: rs547253972) as â€šÃ„ÃºNAâ€šÃ„Ã¹, Clinvitae database (classification likely benign and benign), the ClinVar database (classification benign by Invitae and likely benign by Emory Genetics), the ADPKD Mutation Database (classification indeterminate), and COSMIC (1X in a lung carcinoma). This variant was also identified in the 1000 Genomes Project in 37 of 5000 chromosomes (frequency: 0.0074), HAPMAP-AFR in 32 of 1322 chromosomes (frequency: 0.0242), HAPMAP-AMR in 3 of 694 chromosomes (frequency: 0.0043), HAPMAP-EUR in 2 of 1006 chromosomes (frequency: 0.002), and in the Exome Aggregation Consortium database (August 8th 2016) in 928 of 11372 chromosomes (freq. 0.0816) in the following populations: South Asian in 662 of 7216 chromosomes (freq. 0.09), European (Non-Finnish) in 229 of 3242 chromosomes (freq. 0.07), Other in 8 of 128 chromosomes (freq. 0.06), Latino in 8 of 164 chromosomes (freq. 0.05), African in 16 of 442 chromosomes (freq. 0.04), East Asian in 5 of 172 chromosomes (freq. 0.02) but was not seen in the Finnish populations. This high frequency of observations in a control database strongly suggests that the variant is not clinically significant. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. This variant is an in-frame duplication resulting in the addition of a Glutamic acid residue at codon 102; the impact of this alteration on PKD2 protein function is not known. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Oct 02, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20950398, 17574468, 22863349, 21719175, 22508176) -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PKD2: BS1 -

Polycystic kidney disease 2

Benign:2

Apr 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant polycystic kidney disease

Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PKD2-related disorder

Benign:1

Oct 30, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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