4-88046681-A-G

Variant names:

• chr4-88046681-A-G
• rs17013754
• NM_000297.4:c.1359A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000297.4(PKD2):​c.1359A>G​(p.Pro453Pro) 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:10
• Conservation: PhyloP100: -0.265
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polycystic kidney disease 2

  Inheritance: AD, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 92792.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000297.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	NM_000297.4	MANE Select	c.1359A>G	p.Pro453Pro	synonymous	Exon 6 of 15	NP_000288.1
	PKD2	NM_001440544.1		c.1134A>G	p.Pro378Pro	synonymous	Exon 5 of 14	NP_001427473.1
	PKD2	NR_156488.2		n.1458A>G		non_coding_transcript_exon	Exon 6 of 14

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PKD2	ENST00000237596.7	TSL:1 MANE Select	c.1359A>G	p.Pro453Pro	synonymous	Exon 6 of 15	ENSP00000237596.2
	PKD2	ENST00000508588.5	TSL:2	c.-199+3224A>G		intron	N/A	ENSP00000427131.1

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

GnomAD2 exomes AF: 0.00261 AC: 655 AN: 251404 AF XY: 0.00203

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 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

African (AFR) AF: 0.0325 AC: 1089 AN: 33464

American (AMR) AF: 0.00172 AC: 77 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000823 AC: 71 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00417 AC: 24 AN: 5758

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1111406

Other (OTH) AF: 0.00287 AC: 173 AN: 60354

GnomAD4 genome AF: 0.00920 AC: 1401 AN: 152346 Hom.: 17 Cov.: 32 AF XY: 0.00945 AC XY: 704 AN XY: 74494

African (AFR) AF: 0.0316 AC: 1312 AN: 41568

American (AMR) AF: 0.00327 AC: 50 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68042

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00449 Hom.: 15

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Polycystic kidney disease 2 Benign:3

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Aug 02, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 01, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:3

Sep 21, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 21, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Dec 14, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Polycystic kidney disease Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	8.4
DANN	Benign	0.72
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

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