rs2728118

chr4-88008153-G-Achr4-88008153-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000297.4(PKD2):c.420G>A(p.Gly140=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,462,896 control chromosomes in the GnomAD database, including 9,301 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (929 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8372 hom.)
• Consequence: PKD2 NM_000297.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.02

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 4-88008153-G-A is Benign according to our data. Variant chr4-88008153-G-A is described in ClinVar as [Benign]. Clinvar id is 92795.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88008153-G-A is described in Lovd as [Benign]. Variant chr4-88008153-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD2	NM_000297.4	c.420G>A	p.Gly140=	synonymous_variant	1/15	ENST00000237596.7
PKD2	XM_011532028.3	c.420G>A	p.Gly140=	synonymous_variant	1/14
PKD2	NR_156488.2	n.519G>A		non_coding_transcript_exon_variant	1/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD2	ENST00000237596.7	c.420G>A	p.Gly140=	synonymous_variant	1/15	1	NM_000297.4	P1
	ENST00000662475.1	n.112+213C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0889 AC: 13486 AN: 151746 Hom.: 924 Cov.: 32

Gnomad AFR AF: 0.0280

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.186

Gnomad ASJ AF: 0.0652

Gnomad EAS AF: 0.258

Gnomad SAS AF: 0.0596

Gnomad FIN AF: 0.0735

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0981

Gnomad OTH AF: 0.0795

GnomAD3 exomes AF: 0.133 AC: 11224 AN: 84630 Hom.: 1049 AF XY: 0.118 AC XY: 5664 AN XY: 48146

Gnomad AFR exome AF: 0.0313

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.0654

Gnomad EAS exome AF: 0.290

Gnomad SAS exome AF: 0.0634

Gnomad FIN exome AF: 0.0763

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.115

GnomAD4 exome AF: 0.104 AC: 135815 AN: 1311042 Hom.: 8372 Cov.: 36 AF XY: 0.102 AC XY: 65698 AN XY: 646084

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.257

Gnomad4 ASJ exome AF: 0.0668

Gnomad4 EAS exome AF: 0.306

Gnomad4 SAS exome AF: 0.0613

Gnomad4 FIN exome AF: 0.0753

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.107

GnomAD4 genome AF: 0.0890 AC: 13515 AN: 151854 Hom.: 929 Cov.: 32 AF XY: 0.0906 AC XY: 6721 AN XY: 74224

Gnomad4 AFR AF: 0.0279

Gnomad4 AMR AF: 0.187

Gnomad4 ASJ AF: 0.0652

Gnomad4 EAS AF: 0.259

Gnomad4 SAS AF: 0.0594

Gnomad4 FIN AF: 0.0735

Gnomad4 NFE AF: 0.0981

Gnomad4 OTH AF: 0.0834

Alfa AF: 0.0890 Hom.: 141

Bravo AF: 0.0953

Asia WGS AF: 0.153 AC: 525 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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	Invitae	Jan 31, 2024	- -

Polycystic kidney disease 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 02, 2020	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Sep 07, 2016

- -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD2 p.Gly140Gly variant was identified as a polymorphism in 7 of 172 proband chromosomes (frequency: 0.041) from individuals or families with Autosomal Dominant Polycystic Kidney Disease and (Bataille 2011, Liu 2015). The variant was also identified in dbSNP (ID: rs2728118 “With Benign allele”, with a minor allele frequency of 0.1144 (573 of 5000 chromosomes in the 1000 Genomes Project). This variant was identified in the Exome Aggregation Consortium database (March 14, 2016) in 662 (27 homozygous) of 10588 chromosomes (freq. 0.06 ) in the following populations: East Asian in 32 of 130 chromosomes (freq. 0.25), Latino in 12 of 96 chromosomes (freq. 0.125), other in 10 of 120 chromosomes (freq. 0.08), European (Non-Finnish) in 194 of 2688 chromosomes (freq. 0.07), South Asian in 409 of 7348 chromosomes (freq. 0.06), and African in 5 of 206 chromosomes (freq. 0.02), but was not seen in the Finnish population, increasing the likelihood this could be a low frequency benign variant. In the ClinVar database the variant was identified as benign by Emory Genetics laboratory and in Clinvitae it was identified as benign by EmyClass. In the Mayo Clinic PKD database the variant was identified as likely neutral. In LOVD-PKD2 database the variant was identified 6X and as having no effect. In mRNA transcript analysis in the parents of one patient, the p.Gly140Gly variant occurred in trans to a variant (c.595_595+ 14del) that is predicted to affect splicing and is subjected to nonsense mediated decay (Liu 2015). The p.Gly140Gly 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, 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. -

PKD2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2021

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
BayesDel_noAF	Benign	-0.72
Cadd	Benign	1.6
Dann	Uncertain	0.98
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2728118; hg19: chr4-88929305; COSMIC: COSV52940231; COSMIC: COSV52940231;