rs147654263
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
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
NM_000297.4 missense
Scores
5
4
9
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 GnomAd4 at 460 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: 459AN: 152118Hom.: 3 Cov.: 32
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GnomAD3 exomes AF: 0.00300 AC: 754AN: 251136Hom.: 3 AF XY: 0.00309 AC XY: 419AN XY: 135716
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GnomAD4 exome AF: 0.00279 AC: 4076AN: 1461644Hom.: 12 Cov.: 31 AF XY: 0.00279 AC XY: 2028AN XY: 727126
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GnomAD4 genome AF: 0.00302 AC: 460AN: 152236Hom.: 3 Cov.: 32 AF XY: 0.00390 AC XY: 290AN XY: 74416
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:4
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 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 05, 2024 | - - |
Polycystic kidney disease 2 Benign:3
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 | Fulgent Genetics, Fulgent Genetics | Apr 17, 2022 | - - |
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
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2024 | - - |
Likely benign, criteria provided, single submitter | research | Molecular Genetics of Inherited Kidney Disorders Laboratory, Garvan Institute of Medical Research | Jan 01, 2019 | - - |
not provided Benign:2
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) - |
Benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 06, 2017 | - - |
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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N
REVEL
Uncertain
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
D;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at