NM_144773.4:c.254G>A

Variant names:

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:12U:7

Conservation

PhyloP100: 7.83

Variant links:

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]

PROKR2 links:

Genome browser will be placed here

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: {Likely_pathogenic=6, Uncertain_significance=6, Pathogenic=4}. 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

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROKR2	NM_144773.4 link	c.254G>A	p.Arg85His	missense_variant	Exon 2 of 3	ENST00000678254.1	NP_658986.1	Q8NFJ6A8K1T0
PROKR2	XM_017027646.2 link	c.254G>A	p.Arg85His	missense_variant	Exon 2 of 4		XP_016883135.1	Q8NFJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PROKR2	ENST00000678254.1 link	c.254G>A	p.Arg85His	missense_variant	Exon 2 of 3		NM_144773.4	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4 link	c.254G>A	p.Arg85His	missense_variant	Exon 2 of 3	1		ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1 link	c.146G>A	p.Arg49His	missense_variant	Exon 2 of 3			ENSP00000503366.1	A0A7I2V3D2

Frequencies

GnomAD3 genomes

AF:

0.000828

AC:

126

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000712

AC:

179

AN:

251490

Hom.:

AF XY:

0.000736

AC XY:

100

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.000554

Gnomad NFE exome

AF:

0.00120

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.00119

AC:

1733

AN:

1461876

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

845

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000359

Gnomad4 FIN exome

AF:

0.000431

Gnomad4 NFE exome

AF:

0.00143

Gnomad4 OTH exome

AF:

0.000927

GnomAD4 genome

AF:

0.000828

AC:

126

AN:

152154

Hom.:

Cov.:

AF XY:

0.000915

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.000338

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00135

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000462

Hom.:

Bravo

AF:

0.000718

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.000741

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00142

EpiControl

AF:

0.00142

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

Sep 26, 2019

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 02, 2021

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 11, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Mar 26, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

_x000D_ Criteria applied: PS3, PM5 -

Aug 07, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2Uncertain:3

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 17, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

May 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Male infertility with azoospermia or oligozoospermia due to single gene mutation

Pathogenic:1

Sep 01, 2023

Laan Lab, Human Genetics Research Group, University of Tartu

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Hypogonadism with anosmia

Pathogenic:1

Sep 11, 2019

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 17, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 10, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Mar 08, 2021

Yale Center for Mendelian Genomics, Yale University

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.021

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.55

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.041

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.72

MutationAssessor

Benign

1.9

PrimateAI

Uncertain

0.79

PROVEAN

Uncertain

-4.2

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.91

MVP

0.85

ClinPred

0.17

GERP RS

4.8

Varity_R

0.78

gMVP

0.64

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over