chr20-5302662-C-G

Position:

• chr20-5302662-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PP3

The NM_144773.4(PROKR2):​c.533G>C​(p.Trp178Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000756 in 1,614,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (0 hom.)
• Consequence: PROKR2 NM_144773.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1 B:2
• Conservation: PhyloP100: 7.43

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 Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a disulfide_bond (size 80) in uniprot entity PKR2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_144773.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROKR2	NM_144773.4	c.533G>C	p.Trp178Ser	missense_variant	3/3	ENST00000678254.1	NP_658986.1
PROKR2	XM_017027646.2	c.533G>C	p.Trp178Ser	missense_variant	3/4		XP_016883135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROKR2	ENST00000678254.1	c.533G>C	p.Trp178Ser	missense_variant	3/3		NM_144773.4	ENSP00000504128.1
PROKR2	ENST00000217270.4	c.533G>C	p.Trp178Ser	missense_variant	3/3	1		ENSP00000217270.3
PROKR2	ENST00000678059.1	c.425G>C	p.Trp142Ser	missense_variant	3/3			ENSP00000503366.1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000223 AC: 56 AN: 251460 Hom.: 0 AF XY: 0.000184 AC XY: 25 AN XY: 135900

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00294

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000780 AC: 114 AN: 1461876 Hom.: 0 Cov.: 46 AF XY: 0.0000770 AC XY: 56 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00264

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3 AN XY: 74470

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000907

ExAC AF: 0.000181 AC: 22

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 3 with or without anosmia Pathogenic:2 Uncertain:1 Benign:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	BS1+PS3_Moderate+PS4+PM6+PP4 -
Likely benign, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Oct 19, 2020	Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as likely benign. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Kallmann syndrome (PMID: 29161432, PMID: 18826963). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygotes, compound heterozygotes and homozygous have all been reported and digenic inheritance is also suggested (OMIM). (I) 0112 - The condition associated with this gene has been indicated to have incomplete penetrance. Heterozygotes have been reported as asymptomatic carriers (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to serine. (I) 0251 - This variant is heterozygous. (I) 0308 - Population frequency for this variant is out of keeping with known incidence of Kallmann syndrome. The gnomAD frequency data is skewed towards the East Asian population, with 56 out of 58 global heterozygotes being observed in this subpopulation. This variant is present in 0.3% of the East Asian gnomAD population. (SB) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated 7-transmembrane receptor (NCBI_Conserved_Domains, DECIPHER, RCSB-PDB). (I) 0705 - No missense variants affecting the same amino acid have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in Kallmann syndrome patients (PMID: 30576231, PMID: 30216942), however, it has also been reported in unaffected individuals (PMID: 30487145) and in patients with pathogenic variants in other genes (PMID: 31219235). ClinVar has conflicting interpretation of pathogenicity for this variant, however, the most recent entry is likely benign. To our knowledge, this variant has only been reported in patients from the East Asian region, a region in which this variant is present in the general population. (I) 1010 - Functional evidence for this variant is inconclusive. HEK cell functional analysis indicates that this variant may impair cell surface-targeting of the receptor (PMID: 18826963). (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not provided Pathogenic:1 Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 14, 2023	Identified in patients with hypogonadotropic hypogonadism or hypospadias in published literature who inherited the variant from an unaffected parent, suggesting reduced penetrance or oligogenic inheritance (Aoyama et al., 2017; Zhang et al., 2019; Zhang et al., 2021; Liu et al., 2022); Identified in patients with potentially causative variants in other genes and in one patient with a second PROKR2 variant on the opposite allele (in trans) in published literature, supporting oligogenic or recessive inheritance (Zhao et al., 2019; Zhang et al., 2019; Chen et al., 2020; Liu et al., 2022); Published functional studies demonstrate a damaging effect on transport to the plasma membrane, MAPK signaling, and mobilization of intracellular calcium (Monnier at al., 2009; Cox et al., 2018; Song et al., 2022); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed de novo without confirmed parentage in multiple unrelated patients with Kallmann syndrome or normosmic idiopathic hypogonadotropic hypogonadism in published literature (Liu et al., 2022); This variant is associated with the following publications: (PMID: 22995991, 34489640, 33120852, 34653508, 35669683, 33983622, 18559922, 36317218, 35207461, 36123965, 19707180, 34636164, 35922219, 37122876, 26088945, 24753254, 33968656, 21736917, 32155719, 21664414, 20502053, 35173048, 29161432, 18826963, 26141714, 17054399, 28915117, 30098700, 30487145, 28295047, 33208564, 31219235, 30216942, 32171629, 35090434, 30576231) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 31, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	31
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-12	D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.97
MVP		0.98
ClinPred		0.94	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.96

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: rs201835496; hg19: chr20-5283308;