20-5314116-C-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM5BS1_SupportingBS2

The NM_144773.4(PROKR2):c.254G>T(p.Arg85Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000329 in 1,614,150 control chromosomes in the GnomAD database, including 1 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 0.00041 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

PROKR2
NM_144773.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 7.83

Publications

41 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 -3 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: 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 = 0.000407 (62/152272) while in subpopulation AMR AF = 0.00183 (28/15302). AF 95% confidence interval is 0.0013. There are 1 homozygotes in GnomAd4. There are 32 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 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROKR2	NM_144773.4 link	c.254G>T	p.Arg85Leu	missense_variant	Exon 2 of 3	ENST00000678254.1	NP_658986.1
PROKR2	XM_017027646.2 link	c.254G>T	p.Arg85Leu	missense_variant	Exon 2 of 4		XP_016883135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PROKR2	ENST00000678254.1 link	c.254G>T	p.Arg85Leu	missense_variant	Exon 2 of 3		NM_144773.4	ENSP00000504128.1
PROKR2	ENST00000217270.4 link	c.254G>T	p.Arg85Leu	missense_variant	Exon 2 of 3	1		ENSP00000217270.3
PROKR2	ENST00000678059.1 link	c.146G>T	p.Arg49Leu	missense_variant	Exon 2 of 3			ENSP00000503366.1

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000397

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000326

AC:

AN:

251490

AF XY:

0.000294

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000510

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000321

AC:

469

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

225

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33480

American (AMR)

AF:

0.000760

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000361

AC:

401

AN:

1111998

Other (OTH)

AF:

0.000480

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

112

140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.000407

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

41550

American (AMR)

AF:

0.00183

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.0000943

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000397

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.0000592

Hom.:

Bravo

AF:

0.000895

TwinsUK

AF:

0.000270

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 3 with or without anosmia

Uncertain:3Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

Jan 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Nov 29, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

Jun 10, 2019

New York Genome Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The inherited c.254G>T (p.Arg85Leu) variant in PROKR2 substitutes a highly conserved Arginine for Leucine at amino acid 85/385 (coding exon 2/3). It is found in gnomAD (7 heterozygous individuals, 0 homozygous individuals, allele frequency: 2.2e-4) and ExAC (38 heterozygous individuals, 0 homozygous individuals; allele frequency: 3.13e-4). In silico algorithms predict that this variant is Deleterious (Provean; score: -5.97) and Damaging (SIFT; score: 0.000) to the function of the canonical transcript. This variant is reported in ClinVar with a single submission lacking supporting evidence as Likely Benign (VarID:338863), however different amino acid changes at the same residuehave been reported as Pathogenic, Likely Pathogenic, or as a Variant of Uncertain Significance (p.Arg85His; p.Arg85Gly; Arg85Cys). The Arg85 residue is at the first intracellular loop, and functional studies have suggested that the p.Arg85Leu variant has a mild G-protein coupling defectas well as reduced quantity of protein present at the cell surface [PMID: 24830383].This variant has been identified inindividuals in the literature with Kallmann syndrome or pituitary hormone deficiency [PMID: 24031091; PMID: 23386640]. The inherited c.254G>T (p.Arg85Leu) variant is reported here as a Variant of Uncertain Significance.

not specified

Uncertain:1

Jul 22, 2025

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>T (p.Arg85Leu) results in a non-conservative amino acid change located in the GPCR, rhodopsin-like, 7TM domain (IPR017452) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00033 in 251490 control chromosomes. 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.254G>T has been observed in individual(s) affected with Kallmann Syndrome 3 (McAbe_2013, Sarffati_2013, Bergman_2012, Poch_2024). These data indicate that the variant is likely to be associated with disease. Experimental studies gave conflicting results on the impact of this variant on protein function (Cox_2018, Wang_2023). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 31093944, 22399515, 29161432, 23386640, 38593951, 24031091, 36694982). ClinVar contains an entry for this variant (Variation ID: 338863). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

not provided

Uncertain:1

Oct 22, 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 leucine, which is neutral and non-polar, at codon 85 of the PROKR2 protein (p.Arg85Leu). This variant is present in population databases (rs74315418, gnomAD 0.05%). This missense change has been observed in individual(s) with PROKR2-related conditions (PMID: 20022991, 23386640, 31093944). ClinVar contains an entry for this variant (Variation ID: 338863). 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) indicates that this missense variant is expected to disrupt PROKR2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on PROKR2 function (PMID: 29161432, 36694982). 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.

PROKR2-related disorder

Uncertain:1

Jul 30, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PROKR2 c.254G>T variant is predicted to result in the amino acid substitution p.Arg85Leu. This variant has been reported in the heterozygous state in a patient with Kallmann syndrome (Sarfati et al. 2010. PubMed ID: 20022991, table 2). This variant has also been reported in the heterozygous state in a patient with hypopituitarism and septo-optic dysplasia (McCabe et al. 2013. PubMed ID: 23386640, table 1). In vitro functional assays showed the p.Arg85Leu variant could markedly impair cell surface expression of the receptor when it was tested alone (Sbai et al. 2014. PubMed ID: 24830383; Cox et al. 2018. PubMed ID: 29161432). However, when co-transfected with wild-type and the p.Arg85Leu, the p.Arg85Leu variant could be rescued by the presence of WT PROKR2 in 2 out of 3 signaling pathways, 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). A few different variants affecting the same amino acid (p.Arg85Gly, p.Arg85Cys and p. Arg85His) have been reported in association with Kallman syndrome (Human Gene Mutation Database, HGMD; http://www.hgmd.cf.ac.uk/). This variant is reported in 0.049% of alleles in individuals of European (Non-Finnish) 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

Pathogenic

0.68

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.81

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.7

PhyloP100

7.8

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.0

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Vest4

0.98

ClinPred

0.32

GERP RS

4.8

Varity_R

0.91

gMVP

0.73

Mutation Taster

=6/94

disease causing

(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