rs141090506

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM5PP5BS1_SupportingBS2

The NM_144773.4(PROKR2):c.253C>T(p.Arg85Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00043 in 1,614,178 control chromosomes in the GnomAD database, including 2 homozygotes. 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. R85H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00068 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00040 ( 2 hom. )

Consequence

PROKR2
NM_144773.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:5

Conservation

PhyloP100: 3.08

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 Likely_benign. Variant got -2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-5314116-C-T is described in Lovd as [Likely_pathogenic].

PP5

Variant 20-5314117-G-A is Pathogenic according to our data. Variant chr20-5314117-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 156562.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=2, Likely_pathogenic=2}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000676 (103/152308) while in subpopulation AMR AF= 0.00124 (19/15302). AF 95% confidence interval is 0.000853. There are 0 homozygotes in gnomad4. There are 43 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

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROKR2	NM_144773.4 link	c.253C>T	p.Arg85Cys	missense_variant	2/3	ENST00000678254.1	NP_658986.1	Q8NFJ6A8K1T0
PROKR2	XM_017027646.2 link	c.253C>T	p.Arg85Cys	missense_variant	2/4		XP_016883135.1	Q8NFJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PROKR2	ENST00000678254.1 link	c.253C>T	p.Arg85Cys	missense_variant	2/3		NM_144773.4	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4 link	c.253C>T	p.Arg85Cys	missense_variant	2/3	1		ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1 link	c.145C>T	p.Arg49Cys	missense_variant	2/3			ENSP00000503366.1	A0A7I2V3D2

Frequencies

GnomAD3 genomes

AF:

0.000683

AC:

104

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000592

AC:

149

AN:

251490

Hom.:

AF XY:

0.000603

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00208

Gnomad EAS exome

AF:

0.000217

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000369

Gnomad OTH exome

AF:

0.00195

GnomAD4 exome

AF:

0.000404

AC:

591

AN:

1461870

Hom.:

Cov.:

AF XY:

0.000397

AC XY:

289

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.00264

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000374

Gnomad4 NFE exome

AF:

0.000308

Gnomad4 OTH exome

AF:

0.000878

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152308

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000414

Hom.:

Bravo

AF:

0.000842

ExAC

AF:

0.000502

AC:

EpiCase

AF:

0.000491

EpiControl

AF:

0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 3 with or without anosmia

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 28, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	DASA	Jun 10, 2022	The c.253C>T;p.(Arg85Cys) missense change has been observed in affected individual(s)(PMID: 17054399; 18559922; 18826963; 20502053; 24204987; 25636053; 30430143) - .PS4. The variant is present at low allele frequencies population databases (rs141090506– gnomAD 0.006834%; ABraOM no frequency - http://abraom.ib.usp.br/) -PM2_supporting. Pathogenic missense variant in this residue have been reported and classified as Pathogenic by ACMG criteria (PMID: 17054399; c.254G>A;p.(R85H)) - PM5. In summary, the currently available evidence indicates that the variant is Likely Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 20, 2024	Variant summary: PROKR2 c.253C>T (p.Arg85Cys) 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 0.00059 in 251490 control chromosomes in the gnomAD database, including 2 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in PROKR2 causing Kallmann Syndrome 3, allowing no conclusion about variant significance. c.253C>T has been reported in the literature in individuals affected with features of Kallmann Syndrome such as normosmic idiopathic hypogonadotropic hypogonadism and has been reported among milder variants that may rely upon the genetic context for their phenotypic penetrance (e.g. Cole_2008, Monnier_2009, Moya-Plana_2013, Sarfati_2013, Cox_2018, Zidoune_2022). These reports do not provide unequivocal conclusions about association of the variant with Kallmann Syndrome 3. Publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in impaired G protein-coupling of the receptor and impaired intracellular Ca2+ increase evoked by PROK2 (Monnier_2009), as well as 30.9% of WT cAMP signaling but no effect on two other signaling pathway assays evaluated, namely MAPK and IP-one (Cox_2018). The following publications have been ascertained in the context of this evaluation (PMID: 29161432, 24031091, 18826963, 23082007, 18559922, 36110220). ClinVar contains an entry for this variant (Variation ID: 156562). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 24, 2015	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 25, 2025	Published functional studies demonstrate a damaging effect with impairment of G-protein signaling (PMID: 24830383); Other functional studies indicate that while signaling is impaired, R85C does not impact cell-surface targeting or agonist affinity and likely does not exhibit a dominant negative effect (PMID: 18826963); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23643382, 22745195, 25759380, 21858136, 20696889, 28453858, 29161432, 24031091, 34426522, 30430143, 33098107, 34055685, 33775534, 34348883, 36110220, 35236788, 37338295, 20022991, 34653508, Jimenez_Ruiz_2022, 17054399, 25636053, 23082007, 24204987, 35207461, 36694982, 18559922, 24830383, 18826963, 36843573, 39642868, 38464967, 39459554, 36531499, 30476936, 38614076, 37540677, 39010903) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 85 of the PROKR2 protein (p.Arg85Cys). This variant is present in population databases (rs141090506, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with PROKR2-related conditions (PMID: 2403109, 20022991, 30430143). ClinVar contains an entry for this variant (Variation ID: 156562). Advanced 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 at Invitae 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 are conflicting or provide insufficient evidence to determine the effect of this variant on PROKR2 function (PMID: 18559922, 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. -

Hypogonadotropic hypogonadism 3 without anosmia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 01, 2008

- -

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

- -

PROKR2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2024

The PROKR2 c.253C>T variant is predicted to result in the amino acid substitution p.Arg85Cys. This patient is heterozygous in the PROKR2 gene for a sequence variant defined as c.253C>T, which is predicted to result in the amino acid substitution p.Arg85Cys. This variant has been reported in the heterozygous state in multiple patients with Kallmann syndrome, normosmic hypogonadotropic hypogonadism, or combined pituitary hormone deficiencies (Cole et al. 2008. PubMed ID: 18559922; Monnier et al. 2009. PubMed ID: 18826963; Sykiotis et al. 2010. PubMed ID: 20696889, Table S01 and S02; Miraoui et al. 2013. PubMed ID: 23643382, Table S3; Sarfati et al. 2013. PubMed ID: 24031091; Correa et al. 2015. PubMed ID: 25759380; McCormack et al. 2017. PubMed ID: 28453858). However, this variant has also been reported in healthy first-degree relatives of Kallmann probands and healthy controls (Ruiz-Ferrer et al. 2011. PubMed ID: 21858136; Sarfati et al. 2013. PubMed ID: 24031091; McCormack et al. 2017. PubMed ID: 28453858). In vitro functional studies indicated that the p.Arg85Cys variant could impair G protein coupling of the receptor and moderately compromises receptor signaling through both MAPK and Ca2+ pathways (Cole et al. 2008. PubMed ID: 18559922; Monnier et al. 2009. PubMed ID: 18826963; Sbai et al. 2014. PubMed ID: 24830383). However, other studies showed that the p.Arg85Cys was benign in 2 out of 3 signaling pathways when tested alone, and the p.Arg85Cys variant could be rescued by the presence of WT PROKR2 in cAMP signaling pathway during co-transfection of wild-type and p.Arg85Cys PROKR2, suggesting this variant might be a milder variant that may rely upon the genetic context for its phenotypic penetrance (Cox et al. 2018. PubMed ID: 29161432, Table S2 and Table 1). A few different variants affecting the same amino acid (p.Arg85Gly, p.Arg85Leu and p. Arg85His) have been reported in association with Kallmann syndrome (Human Gene Mutation Database, HGMD; http://www.hgmd.cf.ac.uk/). Of note, while the vast majority of PROKR2 variants associated with hypogonadotropic hypogonadism are heterozygous with no evident mutation on the second allele, biallelic loss-of-function variants in PROKR2 have also been described in association with autosomal recessive hypogonadotropic hypogonadism (Dodé et al. 2006. PubMed ID: 17054399; Cole et al. 2008. PubMed ID: 18559922; Abreu et al. 2008. PubMed ID: 18682503; Tommiska et al. 2013. PubMed ID: 23200691). This variant is reported in 0.22% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.68

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.084

MetaRNN

Uncertain

0.43

MetaSVM

Uncertain

-0.14

MutationAssessor

Pathogenic

3.6

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.94

MVP

0.84

ClinPred

0.12

GERP RS

4.8

Varity_R

0.85

gMVP

0.72

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