rs141090506

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -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. R85G) has been classified as Uncertain significance.

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:6U:5

Conservation

PhyloP100: 3.08

Publications

44 publications found

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 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 3 with or without anosmia
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
septooptic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PROKR2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr20-5314116-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3451.

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 VariationId is 156562.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 103 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROKR2	NM_144773.4 link	c.253C>T	p.Arg85Cys	missense_variant	Exon 2 of 3	ENST00000678254.1	NP_658986.1	Q8NFJ6A8K1T0
PROKR2	XM_017027646.2 link	c.253C>T	p.Arg85Cys	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.253C>T	p.Arg85Cys	missense_variant	Exon 2 of 3		NM_144773.4	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4 link	c.253C>T	p.Arg85Cys	missense_variant	Exon 2 of 3	1		ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1 link	c.145C>T	p.Arg49Cys	missense_variant	Exon 2 of 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

GnomAD2 exomes

AF:

0.000592

AC:

149

AN:

251490

AF XY:

0.000603

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 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

African (AFR)

AF:

0.00119

AC:

AN:

33480

American (AMR)

AF:

0.00148

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00264

AC:

AN:

26134

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000308

AC:

342

AN:

1111990

Other (OTH)

AF:

0.000878

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

119

159

199

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000676

AC:

103

AN:

152308

Hom.:

Cov.:

AF XY:

0.000577

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

41556

American (AMR)

AF:

0.00124

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000294

AC:

AN:

68034

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000533

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:6Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 3 with or without anosmia

Pathogenic:4

Mar 28, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 10, 2022

DASA

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 -

Aug 02, 2024

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 04, 2022

Mendelics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2

Nov 24, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 20, 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.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. -

not provided

Uncertain:2

Dec 04, 2024

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 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). 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 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. -

Jan 25, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Hypogonadotropic hypogonadism 3 without anosmia

Pathogenic:1

Sep 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

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

- -

PROKR2-related disorder

Uncertain:1

May 02, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

3.1

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

Mutation Taster

=30/70

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over