20-5302677-A-C

Position:

• chr20-5302677-A-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1 BP4_Strong BS2

The NM_144773.4(PROKR2):​c.518T>G​(p.Leu173Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,614,222 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0033 (17 hom.)
• Consequence: PROKR2 NM_144773.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:6 B:5
• Conservation: PhyloP100: 8.78

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 -6 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.061356813).
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROKR2	NM_144773.4	c.518T>G	p.Leu173Arg	missense_variant	3/3	ENST00000678254.1	NP_658986.1
PROKR2	XM_017027646.2	c.518T>G	p.Leu173Arg	missense_variant	3/4		XP_016883135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROKR2	ENST00000678254.1	c.518T>G	p.Leu173Arg	missense_variant	3/3		NM_144773.4	ENSP00000504128.1
PROKR2	ENST00000217270.4	c.518T>G	p.Leu173Arg	missense_variant	3/3	1		ENSP00000217270.3
PROKR2	ENST00000678059.1	c.410T>G	p.Leu137Arg	missense_variant	3/3			ENSP00000503366.1

Frequencies

GnomAD3 genomes AF: 0.00212 AC: 322 AN: 152244 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00230 AC: 578 AN: 251442 Hom.: 4 AF XY: 0.00238 AC XY: 324 AN XY: 135896

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00234

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00347

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00326 AC: 4772 AN: 1461860 Hom.: 17 Cov.: 39 AF XY: 0.00320 AC XY: 2329 AN XY: 727230

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00246

Gnomad4 ASJ exome AF: 0.00517

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00382

Gnomad4 OTH exome AF: 0.00348

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152362 Hom.: 1 Cov.: 33 AF XY: 0.00200 AC XY: 149 AN XY: 74508

Gnomad4 AFR AF: 0.000986

Gnomad4 AMR AF: 0.00176

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00335

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.00325 Hom.: 2

Bravo AF: 0.00232

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.00225 AC: 273

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00463

EpiControl AF: 0.00456

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:6 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PROKR2: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 22, 2020	The best available variant frequency is higher than the disease allele frequency; however, this variant is statistically enriched in patients compared to population databases. Variant has been seen homozygously in unaffected individuals. Assessment of experimental evidence suggests this variant results in abnormal protein function. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2024	Reported in the heterozygous, homozygous, or compound heterozygous state in published literature in multiple unrelated patients from different ethnic backgrounds with variable phenotypes, including classic Kallman syndrome with anosmia and hypogonadism, hypogonadotropic hypogonadism, hypothalamic amenorrhea, and gonadotropin-releasing hormone (GnRH) deficiency (PMID: 17054399, 21247312, 22035731, 22773735, 23386640); Published functional studies demonstrate decreased signalling activity secondary to impaired cell-surface targeting of the PROKR2 receptor protein (PMID: 18826963); 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: 22035731, 18723471, 26733480, 28754744, 24276467, 23643382, 22466334, 23386640, 21247312, 27168972, 27899157, 29161432, 29419413, 34426522, 35207461, 35173048, 35236788, 33098107, 34231173, 33401665, Wang2022[case report], 33932486, 36531499, 30476936, 36034425, 32222824, 33988008, 36843573, 35066646, 36138264, 36920900, 25071724, 37338295, 37321569, 36694982, 18826963, 22773735, 17054399) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The PROKR2 p.Leu173Arg variant was identified in several compound heterozygous and homozygous individuals with idiopathic central hypogonadism, as well as a four heterozygous individuals with complex congenital hypopituitarism (Stefanija_2012_PMID:22773735; McCabe_2013_PMID:23386640; Dode_2006_PMID: 17054399; Cole_2008_PMID:18559922). Pathogenic variants in the PROKR2 gene have been reported to associate with the autosomal recessive form of isolated gondotropin-releasing hormone (GnRH) deficiency. In familial cases, this variant is shown to segregate with disease. However, this variant is also seen in unaffected homozygous and heterozygous individuals, which is inconsistent with the autosomal recessive form of GnRH deficiency (McCabe_2013_PMID:23386640; Dode_2006_PMID: 17054399). The variant was identified in dbSNP (ID: rs74315416), LOVD 3.0 and ClinVar (classified as likely benign by Invitae, Illumina and Division of Genomic Diagnostics, Children's Hospital of Philadelphia, as uncertain significance by GeneDx and Mendelics, and as pathogenic by Athena Diagnostics). The variant was identified in control databases in 621 of 282842 chromosomes (4 homozygous) at a frequency of 0.002196 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 65 of 10370 chromosomes (freq: 0.006268), European (non-Finnish) in 429 of 129164 chromosomes (freq: 0.003321), Latino in 81 of 35436 chromosomes (freq: 0.002286), Other in 15 of 7222 chromosomes (freq: 0.002077), African in 21 of 24964 chromosomes (freq: 0.000841), South Asian in 9 of 30616 chromosomes (freq: 0.000294) and European (Finnish) in 1 of 25118 chromosomes (freq: 0.00004), but was not observed in the East Asian population. The p.Leu173 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies reveal that this variant causes impaired protein activity by affecting normal protein localization to the cell surface (Libri_2014_PMID:24276467; Monnier_2009_PMID:18826963; Cole_2008_PMID:18559922). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2009	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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	Revvity Omics, Revvity	Aug 02, 2022	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Nov 10, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 11, 2024	- -

Hypogonadotropic hypogonadism Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

NHS Central & South Genomic Laboratory Hub

Nov 11, 2024

- -

Infertility disorder Uncertain:1

Uncertain significance, no assertion criteria provided

provider interpretation

MAGI's Lab - Research, MAGI Group

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.077	T
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.061	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.6	M
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.027	D
Polyphen		0.99	D
Vest4		0.93
MVP		0.75
ClinPred		0.033	T
GERP RS		5.2
Varity_R		0.78
gMVP		0.81

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: rs74315416; hg19: chr20-5283323; COSMIC: COSV104581449;