chr4-88007816-G-C

Position:

chr4-88007816-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000237596.7(PKD2):c.83G>C(p.Arg28Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.3 in 1,173,158 control chromosomes in the GnomAD database, including 56,509 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R28W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.23 ( 4977 hom., cov: 32)

Exomes 𝑓: 0.31 ( 51532 hom. )

Consequence

PKD2
ENST00000237596.7 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.853

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023896992).

BP6

Variant 4-88007816-G-C is Benign according to our data. Variant chr4-88007816-G-C is described in ClinVar as [Benign]. Clinvar id is 92798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88007816-G-C is described in Lovd as [Likely_benign]. Variant chr4-88007816-G-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.319 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4 linkuse as main transcript	c.83G>C	p.Arg28Pro	missense_variant	1/15	ENST00000237596.7	NP_000288.1	Q13563-1Q9UEU6
PKD2	XM_011532028.3 linkuse as main transcript	c.83G>C	p.Arg28Pro	missense_variant	1/14		XP_011530330.1
PKD2	NR_156488.2 linkuse as main transcript	n.182G>C		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 linkuse as main transcript	c.83G>C	p.Arg28Pro	missense_variant	1/15	1	NM_000297.4	ENSP00000237596.2		Q13563-1
ENSG00000286618	ENST00000662475.1 linkuse as main transcript	n.112+550C>G		intron_variant

Frequencies

GnomAD3 genomes

AF:

0.234

AC:

34796

AN:

148556

Hom.:

4976

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.355

Gnomad AMR

AF:

0.220

Gnomad ASJ

AF:

0.272

Gnomad EAS

AF:

0.00157

Gnomad SAS

AF:

0.164

Gnomad FIN

AF:

0.337

Gnomad MID

AF:

0.252

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.246

GnomAD3 exomes

AF:

0.377

AC:

345

AN:

916

Hom.:

AF XY:

0.379

AC XY:

216

AN XY:

570

show subpopulations

Gnomad AFR exome

AF:

0.750

Gnomad AMR exome

AF:

0.276

Gnomad ASJ exome

AF:

0.500

Gnomad SAS exome

AF:

0.231

Gnomad FIN exome

AF:

0.524

Gnomad NFE exome

AF:

0.385

Gnomad OTH exome

AF:

0.444

GnomAD4 exome

AF:

0.310

AC:

317470

AN:

1024494

Hom.:

51532

Cov.:

AF XY:

0.310

AC XY:

150572

AN XY:

485552

show subpopulations

Gnomad4 AFR exome

AF:

0.0944

Gnomad4 AMR exome

AF:

0.183

Gnomad4 ASJ exome

AF:

0.273

Gnomad4 EAS exome

AF:

0.000920

Gnomad4 SAS exome

AF:

0.173

Gnomad4 FIN exome

AF:

0.357

Gnomad4 NFE exome

AF:

0.328

Gnomad4 OTH exome

AF:

0.265

GnomAD4 genome

AF:

0.234

AC:

34790

AN:

148664

Hom.:

4977

Cov.:

AF XY:

0.232

AC XY:

16839

AN XY:

72508

show subpopulations

Gnomad4 AFR

AF:

0.103

Gnomad4 AMR

AF:

0.219

Gnomad4 ASJ

AF:

0.272

Gnomad4 EAS

AF:

0.00157

Gnomad4 SAS

AF:

0.165

Gnomad4 FIN

AF:

0.337

Gnomad4 NFE

AF:

0.322

Gnomad4 OTH

AF:

0.243

Alfa

AF:

0.175

Hom.:

409

Bravo

AF:

0.214

TwinsUK

AF:

0.322

AC:

1195

ALSPAC

AF:

0.324

AC:

1248

ExAC

AF:

0.0532

AC:

189

Asia WGS

AF:

0.0790

AC:

258

AN:

3246

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 05, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Autosomal dominant polycystic kidney disease

Benign:2

Benign, criteria provided, single submitter	research	Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Polycystic kidney disease 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 07, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD2 p.Arg28Pro variant was identified in 2 of 126 proband chromosomes (frequency: 0.016) from Slovenian and French individuals or families with ADPKD (Vouk 2006, Bataille 2011). The variant was also identified as a polymorphism in Czech families with ADPKD, with frequency not specified (Reiterova 2002, Stekrova 2004). In a European study, screening the variant in 15 affected individuals and 25 unaffected individuals, yielded a heterozygosity of 0.49, or no difference in frequency between the two groups (Torra 1999). In another study, the variant was found to co-occur with a pathogenic PKD2 variant (c.196_199dup, p.P67fsX26) in 1 affected patient, increasing the likelihood that the p.Arg28Pro variant does not have clinical significance (Tan 2009). The variant was also identified in dbSNP (ID: rs1805044) as â€šÃ„ÃºWith benign alleleâ€šÃ„Ã¹, 1000 Genomes Project in 724 of 5007 chromosomes (frequency: 0.1446), the Exome Aggregation Consortium database (March 14, 2016) in 12 of 78 chromosomes (frequency: 0.1538) or 12 alleles (1 homozygote) from a population of South Asian individuals and none from European (Non-Finnish), East Asian, Other, African, Latino, or European (Finnish) individuals. The variant was identified in Clinvitae and the ClinVar database (classified as benign by Emory Genetics), and the ADPKD Mutation Database (classification likey neutral). The p.Arg28 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.56

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.90

PROVEAN

Benign

-0.40

REVEL

Benign

0.046

Sift

Uncertain

0.012

Sift4G

Benign

0.29

Polyphen

0.15

Vest4

0.084

MPC

0.77

ClinPred

0.037

GERP RS

0.55

Varity_R

0.21

gMVP

0.31

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