rs17013754

chr4-88046681-A-Gchr4-88046681-A-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.265

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High AC in GnomAd at 1392 AD gene.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00914 AC: 1392 AN: 152228 Hom.: 17 Cov.: 32

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.: 6 AF XY: 0.00203 AC XY: 276 AN XY: 135870

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.: 16 Cov.: 30 AF XY: 0.000923 AC XY: 671 AN XY: 726950

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.: 17 Cov.: 32 AF XY: 0.00945 AC XY: 704 AN XY: 74494

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.: 4

Bravo AF: 0.0106

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	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. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 01, 2022	- -

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	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 21, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2020	- -

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 “With Benign allele.” 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

Invitae

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

Other links and lift over

dbSNP: rs17013754; hg19: chr4-88967833; COSMIC: COSV99418196; COSMIC: COSV99418196;