rs147654263

chr4-88067959-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000297.4(PKD2):c.2420G>A(p.Arg807Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 1,613,880 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (12 hom.)
• Consequence: PKD2 NM_000297.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 9.31

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008992344).
• BP6: Variant 4-88067959-G-A is Benign according to our data. Variant chr4-88067959-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 220091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-88067959-G-A is described in Lovd as [Likely_benign]. Variant chr4-88067959-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00302 (460/152236) while in subpopulation AMR AF= 0.00432 (66/15292). AF 95% confidence interval is 0.00348. There are 3 homozygotes in gnomad4. There are 290 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 459 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PKD2	NM_000297.4	c.2420G>A	p.Arg807Gln	missense_variant	13/15	ENST00000237596.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PKD2	ENST00000237596.7	c.2420G>A	p.Arg807Gln	missense_variant	13/15	1	NM_000297.4	P1

Frequencies

GnomAD3 genomes AF: 0.00302 AC: 459 AN: 152118 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00213

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00300 AC: 754 AN: 251136 Hom.: 3 AF XY: 0.00309 AC XY: 419 AN XY: 135716

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00205

Gnomad ASJ exome AF: 0.00457

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00279 AC: 4076 AN: 1461644 Hom.: 12 Cov.: 31 AF XY: 0.00279 AC XY: 2028 AN XY: 727126

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.00252

Gnomad4 OTH exome AF: 0.00263

GnomAD4 genome AF: 0.00302 AC: 460 AN: 152236 Hom.: 3 Cov.: 32 AF XY: 0.00390 AC XY: 290 AN XY: 74416

Gnomad4 AFR AF: 0.000650

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00403

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.00215

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00224 Hom.: 1

Bravo AF: 0.00221

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00277 AC: 336

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 22, 2019	- -

Polycystic kidney disease 2 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Autosomal dominant polycystic kidney disease Benign:2

Likely 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 26, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 17, 2020	Identified in a family with polycystic kidney disease (Magistroni et al., 2003); however, additional reports classify R807Q as indeterminate (Rossetti et al., 2007; Neumann et al., 2013); Functional study showed R807Q had no affect on the coiled-coil domain and interaction, and variant was classified as likely polymorphism (Giamarchi et al., 2010).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23300259, 22863349, 17582161, 20168298, 12707387, 26692149) -

Polycystic kidney disease Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The PKD2 p.Arg807Gln variant was identified in 6 of 3926 proband chromosomes (frequency: 0.002) from individuals or families with ADPKD (Magistroni 2003, Robinson 2012, Neumann 2013, Rossetti 2007, Rossetti 2012). The variant was also identified in the following databases: dbSNP (ID: rs147654263) as “With other allele”, ClinVar (classified as benign by Invitae and Children Mercy hospital; as likely benign by Prevention Genetics and Illumina; and as uncertain significance by GeneDx), LOVD 3.0 (1x, reported as "does not affect protein”), ADPKD Mutation Database (as likely neutral). The variant was not identified in PKD1-LOVD database. The variant was identified in control databases in 875 (4 homozygous) of 276852 chromosomes at a frequency of 0.003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was observed in the following populations: African in 9 of 24032 chromosomes (freq. 0.0004), Other in 27 of 6462 chromosomes (freq. 0.004), Latino in 70 of 34396 chromosomes (freq. 0.002), European in 289 (1 homozygous) of 126416 chromosomes (freq. 0.002), Ashkenazi Jewish in 47 of 10138 chromosomes (freq. 0.005), East Asian in 1 of 18838 chromosomes (freq. 0.00005), Finnish in 431 (3 homozygous) of 25788 chromosomes (freq. 0.02), and South Asian in 1 of 30782 chromosomes (freq. 0.00003). The p.Arg807Gln 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. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. A functional study showed R807Q had no effect on the coiled-coil domain; the variant was identified as likely polymorphism (Giamarchi 2010). 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	0.33
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Pathogenic	0.18
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T;T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;.;D
MetaRNN	Benign	0.0090	T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	1.9	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.56	N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.23	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.89
MVP		0.86
MPC		0.67
ClinPred		0.044	T
GERP RS		5.7
Varity_R		0.10
gMVP		0.36

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: rs147654263; hg19: chr4-88989111;