chr20-5314116-C-A

Position:

chr20-5314116-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM5BS1_Supporting

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. R85H) has been classified as Likely pathogenic.

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:5B:1

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-T is described in Lovd as [Likely_pathogenic].

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 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/exons	MANE	Protein	UniProt
PROKR2	NM_144773.4 link	c.254G>T	p.Arg85Leu	missense_variant	2/3	ENST00000678254.1	NP_658986.1	Q8NFJ6A8K1T0
PROKR2	XM_017027646.2 link	c.254G>T	p.Arg85Leu	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.254G>T	p.Arg85Leu	missense_variant	2/3		NM_144773.4	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4 link	c.254G>T	p.Arg85Leu	missense_variant	2/3	1		ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1 link	c.146G>T	p.Arg49Leu	missense_variant	2/3			ENSP00000503366.1	A0A7I2V3D2

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

GnomAD3 exomes

AF:

0.000326

AC:

AN:

251490

Hom.:

AF XY:

0.000294

AC XY:

AN XY:

135922

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000361

Gnomad4 OTH exome

AF:

0.000480

GnomAD4 genome

AF:

0.000407

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000430

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000397

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.000895

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 3 with or without anosmia

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 21, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 10, 2019	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

Uncertain significance, criteria provided, single submitter

clinical testing

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

Sep 03, 2024

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. 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 0.00033 in 251490 control chromosomes (gnomAD v2) and one homozygote in gnomAD v4 database. c.254G>T has been reported in the literature the heterozygous state in individuals affected with Kallmann Syndrome or hypopituitarism (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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

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). 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) performed at Invitae indicates that this missense variant is expected to disrupt PROKR2 protein function. 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

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 30, 2024

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

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.57

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.7

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.0

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.98

MVP

0.83

ClinPred

0.32

GERP RS

4.8

Varity_R

0.91

gMVP

0.73

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