rs141090506

chr20-5314117-G-Achr20-5314117-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM5 PP5 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:4
• Conservation: PhyloP100: 3.08

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 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 id is 3451.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=6, Uncertain_significance=5, Pathogenic=4}.
• 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=1}.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROKR2	ENST00000678254.1	c.253C>T	p.Arg85Cys	missense_variant	2/3		NM_144773.4	P1
PROKR2	ENST00000217270.4	c.253C>T	p.Arg85Cys	missense_variant	2/3	1		P1
PROKR2	ENST00000678059.1	c.145C>T	p.Arg49Cys	missense_variant	2/3

Frequencies

GnomAD3 genomes AF: 0.000683 AC: 104 AN: 152190 Hom.: 0 Cov.: 32

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.: 2 AF XY: 0.000603 AC XY: 82 AN XY: 135922

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.: 2 Cov.: 34 AF XY: 0.000397 AC XY: 289 AN XY: 727240

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.: 0 Cov.: 32 AF XY: 0.000577 AC XY: 43 AN XY: 74480

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.: 0

Bravo AF: 0.000842

ExAC AF: 0.000502 AC: 61

EpiCase AF: 0.000491

EpiControl AF: 0.000652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 3 with or without anosmia Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
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 -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 24, 2023	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 does not allow conclusions about variant significance. c.253C>T has been reported in the literature in multiple 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 (example, Monnier_2009, Sarfati_2013, Moya-Plana_2013, Cox_2018). However, these report(s) do not provide unequivocal conclusions about association of the variant with Kallmann Syndrome 3. At least two publications report experimental evidence evaluating an impact on protein function (example, Monnier_2009 and Cox_2018). 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, 18826963, 23082007, 24031091). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (LP/P, n=3; VUS, n=3). At-least one of these submitters has re-classified this variant from Likely pathogenic to VUS since our initial evaluation. All submitters cite overlapping evidence utilized in the context of this evaluation. 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	Jul 18, 2023	Observed in the homozygous and heterozygous state in individuals with features of Kallman syndrome (Cole et al., 2008; Sarfati et al., 2013; Miraoui et al., 2013); Published functional studies demonstrate a damaging effect (impairment of G-protein signaling) (Sbai et al., 2014); 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 (Monnier et al., 2009); 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, 18559922, 30430143, 33098107, 34055685, 36110220, 35236788, 37338295, 20022991, 34653508, Jimenez_Ruiz_2022, 17054399, 25636053, 23082007, 24204987, 35207461, 36694982, 24830383, 18826963) -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.68	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.6	H
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.94
MVP		0.84
ClinPred		0.12	T
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

Other links and lift over

dbSNP: rs141090506; hg19: chr20-5294763; COSMIC: COSV54086348;