20-5302137-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS1_Supporting

The NM_144773.4(PROKR2):c.1058G>A(p.Arg353His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

PROKR2
NM_144773.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 0.508

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 -3 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.113286436).

BS1

Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000677 (99/1461882) while in subpopulation EAS AF= 0.000907 (36/39700). AF 95% confidence interval is 0.000673. There are 0 homozygotes in gnomad4_exome. There are 40 alleles in male gnomad4_exome 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 rank	MANE	Protein	UniProt
PROKR2	NM_144773.4 link	c.1058G>A	p.Arg353His	missense_variant	Exon 3 of 3	ENST00000678254.1	NP_658986.1	Q8NFJ6A8K1T0
PROKR2	XM_017027646.2 link	c.1058G>A	p.Arg353His	missense_variant	Exon 3 of 4		XP_016883135.1	Q8NFJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PROKR2	ENST00000678254.1 link	c.1058G>A	p.Arg353His	missense_variant	Exon 3 of 3		NM_144773.4	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4 link	c.1058G>A	p.Arg353His	missense_variant	Exon 3 of 3	1		ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1 link	c.950G>A	p.Arg317His	missense_variant	Exon 3 of 3			ENSP00000503366.1	A0A7I2V3D2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251478

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000677

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000907

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.0000423

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000579

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 09, 2025	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 353 of the PROKR2 protein (p.Arg353His). This variant is present in population databases (rs576243101, gnomAD 0.04%). This missense change has been observed in individual(s) with Kallmann syndrome and/or nonobstructive azoospermia (PMID: 30576231, 36259570). ClinVar contains an entry for this variant (Variation ID: 1012475). 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 not expected to disrupt PROKR2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects PROKR2 function (PMID: 30576231). 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	Published functional studies demonstrate a damaging effect (Zhao et al., 2019); This variant is associated with the following publications: (PMID: 31748124, 30576231, 30602096, 34636164) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 25, 2023

Variant summary: PROKR2 c.1058G>A (p.Arg353His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251478 control chromosomes in the gnomAD database and at a frequency of 0.00068, including 72 heterozygotes and one homozygote, in the ToMMo 54KJPN dataset of East Asian control individuals. This frequency suggests the variant is not likely associated with a highly penetrant autosomal dominant condition and may be a benign polymorphism found primarily in individuals of East Asian ancestry. c.1058G>A has been reported in the literature in two Chinese individuals affected with Kallmann Syndrome 3 (Zhao_2019, Men_2020, Wang_2023). One of these individuals also had a variant in the FGFR1 gene which was suggested may contribute to the disease phenotype, possibly in an additive manner as the PROKR2 and FGFR1 variants were each inherited from an unaffected parent (Men_2020). c.1058G>A has also been reported in the heterozygous state as a VUS in an individual with nonobstructive azoospermia who did not have a clinical diagnosis of Kallmann Syndrome (Liu_2023). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found the variant had normal cell surface expression and Gas signaling, but ERK1/2 signaling and Gaq-dependent signaling was decreased to approximately 50% compared to the wild type (Zhao_2019). The following publications have been ascertained in the context of this evaluation (PMID: 36259570, 31748124, 30576231, 36694982). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Hypogonadotropic hypogonadism 3 with or without anosmia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 16, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.10

Eigen

Benign

0.083

Eigen_PC

Benign

0.046

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.60

M_CAP

Benign

0.015

MetaRNN

Benign

0.11

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.2

REVEL

Benign

0.12

Sift

Benign

0.19

Sift4G

Benign

0.15

Polyphen

0.92

Vest4

0.24

MVP

0.71

ClinPred

0.14

GERP RS

4.1

Varity_R

0.053

gMVP

0.74

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