chr20-5314116-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM5PP5BP4BS1_Supporting
The NM_144773.4(PROKR2):c.254G>A(p.Arg85His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,614,030 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R85L) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00083 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0012 ( 1 hom. )
Consequence
PROKR2
NM_144773.4 missense
NM_144773.4 missense
Scores
6
6
7
Clinical Significance
Conservation
PhyloP100: 7.83
Genes affected
PROKR2 (HGNC:15836): (prokineticin receptor 2) Prokineticins are secreted proteins that can promote angiogenesis and induce strong gastrointestinal smooth muscle contraction. The protein encoded by this gene is an integral membrane protein and G protein-coupled receptor for prokineticins. The encoded protein is similar in sequence to GPR73, another G protein-coupled receptor for prokineticins. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM5
Other missense variant is known to change same aminoacid residue: Variant chr20-5314116-C-A is described in Lovd as [Pathogenic].
PP5
Variant 20-5314116-C-T is Pathogenic according to our data. Variant chr20-5314116-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3451.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=4, Uncertain_significance=6, Likely_pathogenic=6}. Variant chr20-5314116-C-T is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.30555734). . Strength limited to SUPPORTING due to the PP5.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000828 (126/152154) while in subpopulation NFE AF= 0.00135 (92/68044). AF 95% confidence interval is 0.00113. There are 0 homozygotes in gnomad4. There are 68 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PROKR2 | ENST00000678254.1 | c.254G>A | p.Arg85His | missense_variant | 2/3 | NM_144773.4 | ENSP00000504128.1 | |||
| PROKR2 | ENST00000217270.4 | c.254G>A | p.Arg85His | missense_variant | 2/3 | 1 | ENSP00000217270.3 | |||
| PROKR2 | ENST00000678059.1 | c.146G>A | p.Arg49His | missense_variant | 2/3 | ENSP00000503366.1 |
Frequencies
GnomAD3 genomes 0.000828 AC: 126AN: 152154Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000712 AC: 179AN: 251490Hom.: 0 AF XY: 0.000736 AC XY: 100AN XY: 135922
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GnomAD4 exome AF: 0.00119 AC: 1733AN: 1461876Hom.: 1 Cov.: 34 AF XY: 0.00116 AC XY: 845AN XY: 727244
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GnomAD4 genome 0.000828 AC: 126AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.000915 AC XY: 68AN XY: 74316
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:12Uncertain:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hypogonadotropic hypogonadism 3 with or without anosmia Pathogenic:7Uncertain:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2009 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Sep 26, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Aug 07, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This variant has been previously reported in the literature in association with a range of phenotypes that include septo-optic dysplasia (SOD), combined pituitary hormone deficiency (CPHD), hypothalamic amenorrhea, Hypopituitarism with pituitary stalk interruption, Hirschsprung disease, and Kallman syndrome (PMID: 22319038, 21247312, 21858136, 22466334, 20022991, 17054399, 30487145). Inheritance studies showed that the c.254G>A (p.Arg85His) variant is often inherited from an unaffected parent and/or detected in other unaffected family members, which suggests incomplete penetrance (PMID: 21247312, 22466334). Additionally, one individual was reported with the c.254G>A (p.Arg85His) variant and another variant in a gene associated with pituitary hormone deficiency (PMID: 22319038). Functional studies showed that the presence of this variant resulted in a mild damaging effect on receptor signaling activity (PMID: 21247312, 24830383, 29161432, 18826963). However, recent functional studies suggest the c.254G>A (p.Arg85His) variant is only damaging in the homozygous state (PMID: 29161432). A different nucleotide change at the same position (c.254G>T, p.Arg85Leu) has been reported as a heterozygous change in individuals with Kallman syndrome, combined pituitary hormone deficiency, GH deficiency, TSH deficiency and ACTH deficiency affected individuals (PMID: 23386640, 20022991). The c.254G>A (p.Arg85His) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.075% (212/282884) and is absent in the homozygous state. The c.254G>A (p.Arg85His) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.254G>A (p.Arg85His) variant is classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Sep 29, 2022 | _x000D_ Criteria applied: PS3, PM5 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 02, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jun 11, 2020 | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as likely pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene (PMID:18826963). (N) 0104 - Dominant Negative is a mechanism of disease for this gene (PMID:29161432). (N) 0108 - This gene is known to be associated with both recessive and dominant disease, where recessive is more penetrant and severe (OMIM). (N) 0112 - Variants in this gene are known to have reduced penetrance for heterozygous carriers (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from arginine to histidine. THis variant is in exon 2 of the PROKR2 gene. (N) 0251 - Variant is heterozygous. (N) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (166 heterozygote, 2 homozygotes). (N) 0310 - Variant is present in gnomAD >=0.001 and 0.01 for a dominant condition (212 heterozygote, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0600 - Variant is located in an annotated domain or motif, (7 transmembrane receptor; PDB). (N) 0703 - Comparable variants have moderate previous evidence for pathogenicity. Alternative changes (p.Arg85Leu, p.Arg85Gly) have been reported as likely benign but mostly pathogenic (ClinVar, PMID:29161432, PMID:20022991, PMID:31093944) in patients with Kallman syndrome. An additional alternative change (p.Arg85Cys) (P) 0802 - Moderate previous evidence of pathogenicity. This variant has been described as both VUS and pathogenic (ClinVar, LOVD). However, it has been reported in multiple unrelated heterozygous patients as well as a homozygote patient, with Kallman syndrome (PMID:29161432, PMID:17054399, PMID:22466334). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional analysis showed a significant reduction in calcium mobilization, MAPK signal activation and whole cell protein expression (PMID:18826963, PMID: 18682503). (P) 1208 – Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign - |
not provided Pathogenic:2Uncertain:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 28, 2024 | Published functional studies demonstrate impaired G-protein signaling (PMID: 18826963, 24830383); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21247312, 23643382, 21858136, 24830383, 22745195, 22319038, 26207952, 22466334, 29161432, 32870266, 34198905, 30487145, 28807454, 34426522, 33775534, 35669683, 33098107, 17054399, 36694982, 31093944, 35236788, 18682503, 37122876, 37321569, 37019085, 37338295, 20022991, 18826963, 37432431, 30476936, 30921766, 37540677) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2025 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 85 of the PROKR2 protein (p.Arg85His). This variant is present in population databases (rs74315418, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with autosomal recessive Kallmann syndrome and/or autosomal dominant combined pituitary hormone deficiency (PMID: 17054399, 33098107, 37432431). ClinVar contains an entry for this variant (Variation ID: 3451). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROKR2 protein function. Experimental studies have shown that this missense change affects PROKR2 function (PMID: 18826963, 22745195, 24830383, 29161432). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2019 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 17, 2015 | - - |
Male infertility with azoospermia or oligozoospermia due to single gene mutation Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Laan Lab, Human Genetics Research Group, University of Tartu | Sep 01, 2023 | - - |
Hypogonadism with anosmia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital | Sep 11, 2019 | This is a recurrent pathogenic variant that is known to exhibit incomplete penetrance and variable expressivity. This change has been reported in individuals with Kallmann syndrome (KS), normosmic isolated gonadotropin-releasing hormone deficiency (IGD), anosomia, hypopituitarism, and hypothalamic amenorrhea; but is also present in many phenotypically normal individuals (PMID: 23596439, PMID: 20022991, PMID: 21247312, PMID: 22319038, PMID: 22466334, PMID: 23082007, PMID: 23643382). The c.254G>A variant, located in exon 2 of PROKR2, substitutes the arginine with histidine at position 85 of the protein. This variant is found in individuals with European ancestry with an allele frequency of ~0.12% (161/129,188 alleles) in the Genome Aggregation Database. This frequency is due to a common founder allele (PMID: 26207952). The p.Arg85His change has been demonstrated to cause a loss of function in in vitro assays (PMID: 18826963, PMID: 29161432). - |
PROKR2-related disorder Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 17, 2023 | The PROKR2 c.254G>A variant is predicted to result in the amino acid substitution p.Arg85His. This variant has been reported in the heterozygous and homozygous states in many individuals with Kallmann syndrome and hypogonadotropic hypogonadism (Dodé et al 2006. PubMed ID: 17054399; Sarfati et al. 2010. PubMed ID: 20022991; Table S3, Miraoui et al. 2013. PubMed ID: 23643382; Choi et al. 2015. PubMed ID: 26207952; Hacquart et al. 2017. PubMed ID: 28807454; Kałużna et al. 2021. PubMed ID: 34198905; Cho et al. 2021. PubMed ID: 33775534). This variant has also been reported in individuals with hypopituitarism and hypothalamic amenorrhea (Reynaud et al. 2012. PubMed ID: 22466334; Jullien et al. 2020. PubMed ID: 33098107; Caronia et al. 2011. PubMed ID: 21247312; Delaney et al. 2020. PubMed ID: 32870266). Functional studies showed that this variant impairs Gq-dependent signaling activity and decreases PROKR2 expression when tested alone, but when co-transfected with wild type, only 2 of 3 signaling assays showed loss of function (Monnier et al. 2009. PubMed ID: 18826963; Caronia et al. 2011. PubMed ID: 21247312; Reynaud et al. 2012. PubMed ID: 22466334; Cox et al. 2018. PubMed ID: 29161432). This variant is reported in 0.12% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-5294762-C-T), and is present in asymptomatic family members (Caronia et al. 2011. PubMed ID: 21247312; Reynaud et al. 2012. PubMed ID: 22466334). Based on the available evidence, this variant is classified as likely pathogenic. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 10, 2024 | Variant summary: PROKR2 c.254G>A (p.Arg85His) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 251490 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database exceeds the estimated maximal expected allele frequency for a pathogenic variant in PROKR2 causing Kallmann Syndrome 3 phenotype. c.254G>A has been reported in the literature in multiple individuals affected with Kallmann Syndrome 3 (Dod_2006, Monnier_2009, Sarfati_2013, Cox_2018). These data indicate that the variant is very likely to be associated with disease. At least three publication reports experimental evidence evaluating an impact on protein function and interferes only modestly with receptor function (Monnier_2009, Abreu_2012, Reynaud_2012). The following publications have been ascertained in the context of this evaluation (PMID: 22745195, 29161432, 17054399, 18826963, 22466334, 24031091). ClinVar contains an entry for this variant (Variation ID: 3451). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Amenorrhea Uncertain:1
| Uncertain significance, no assertion criteria provided | literature only | Yale Center for Mendelian Genomics, Yale University | Mar 08, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Benign
L
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
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