rs17013754

Positions:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000297.4(PKD2):c.1359A>G(p.Pro453=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,613,526 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0092 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 16 hom. )

Consequence

PKD2
NM_000297.4 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.265

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.43).

BP6

Variant 4-88046681-A-G is Benign according to our data. Variant chr4-88046681-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 92792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88046681-A-G is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.265 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0092 (1401/152346) while in subpopulation AFR AF= 0.0316 (1312/41568). AF 95% confidence interval is 0.0301. There are 17 homozygotes in gnomad4. There are 704 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1401 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PKD2	NM_000297.4 linkuse as main transcript	c.1359A>G	p.Pro453=	synonymous_variant	6/15	ENST00000237596.7	NP_000288.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PKD2	ENST00000237596.7 linkuse as main transcript	c.1359A>G	p.Pro453=	synonymous_variant	6/15	1	NM_000297.4	ENSP00000237596	P1	Q13563-1
PKD2	ENST00000508588.5 linkuse as main transcript	c.-199+3224A>G		intron_variant		2		ENSP00000427131

Frequencies

GnomAD3 genomes

AF:

0.00914

AC:

1392

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0314

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00621

GnomAD3 exomes

AF:

0.00261

AC:

655

AN:

251404

Hom.:

AF XY:

0.00203

AC XY:

276

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0336

Gnomad AMR exome

AF:

0.00156

Gnomad ASJ exome

AF:

0.000496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000784

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00103

AC:

1500

AN:

1461180

Hom.:

Cov.:

AF XY:

0.000923

AC XY:

671

AN XY:

726950

show subpopulations

Gnomad4 AFR exome

AF:

0.0325

Gnomad4 AMR exome

AF:

0.00172

Gnomad4 ASJ exome

AF:

0.000689

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000823

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000432

Gnomad4 OTH exome

AF:

0.00287

GnomAD4 genome

AF:

0.00920

AC:

1401

AN:

152346

Hom.:

Cov.:

AF XY:

0.00945

AC XY:

704

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.0316

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000132

Gnomad4 OTH

AF:

0.00615

Alfa

AF:

0.00227

Hom.:

Bravo

AF:

0.0106

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2017	- -

Polycystic kidney disease 2

Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 02, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 01, 2022	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 14, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Polycystic kidney disease

Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The PKD2 p.Pro453Pro variant was not identified in the literature nor was it identified in the PKD2-LOVD database. The variant was identified in dbSNP (ID: rs17013754) as â€šÃ„ÃºWith Benign allele.â€šÃ„Ã¹ This variant was identified in the 1000 Genomes Project in 60 of 5000 chromosomes (frequency: 0.012); The HAPMAP-YRI in 6 of 114 chromosomes (frequency: 0.05263158); NHLBI GO Exome Sequencing Project in 2 of 8600 European American (frequency: 0.000232558), and 133 of 4406 African American alleles (frequency: 0.03018611); Exome Aggregation Consortium database (August 8, 2016) in 388 (6 homozygous) of 121396 chromosomes (frequency: 0.003196) in the following populations: African in 346 of 10406 chromosomes (frequency: 0.03325) Latino in 17 of 11572 chromosomes (frequency: 0.001469) South Asian in 13 of 16510 chromosomes (frequency: 0.0007874) European (Non-Finnish) in 9 of 66734 chromosomes (frequency: 0.0001349), and Other in 3 of 908 chromosomes (frequency0.003304) but was not seen in East Asian and European (Finnish) populations, increasing the likelihood this could be a low frequency benign variant; ClinVar and Clinvitae database (Benign by Emory Genetics, Invitae, and Prevention Genetics); GeneInsight COGR database (benign by LMM) and ADPKD Mutation Database (Likely neutral). The p.Pro453Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, and HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, this variant meets our laboratory criteria to be classified as benign. -

Autosomal dominant polycystic kidney disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.43

CADD

Benign

8.4

DANN

Benign

0.72

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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