chr20-5314311-TG-T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_144773.4(PROKR2):c.58delC(p.His20MetfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000205 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

PROKR2
NM_144773.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12U:2

Conservation

PhyloP100: 0.978

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 Pathogenic. Variant got 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.

PP5

Variant 20-5314311-TG-T is Pathogenic according to our data. Variant chr20-5314311-TG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-5314311-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROKR2	NM_144773.4 link	c.58delC	p.His20MetfsTer24	frameshift_variant	Exon 2 of 3	ENST00000678254.1	NP_658986.1	Q8NFJ6A8K1T0
PROKR2	XM_017027646.2 link	c.58delC	p.His20MetfsTer24	frameshift_variant	Exon 2 of 4		XP_016883135.1	Q8NFJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PROKR2	ENST00000678254.1 link	c.58delC	p.His20MetfsTer24	frameshift_variant	Exon 2 of 3		NM_144773.4	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4 link	c.58delC	p.His20MetfsTer24	frameshift_variant	Exon 2 of 3	1		ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1 link	c.-22-29delC		intron_variant	Intron 1 of 2			ENSP00000503366.1	A0A7I2V3D2

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152064

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000103

AC:

AN:

251478

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000173

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000204

AC:

298

AN:

1461894

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

119

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000253

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000217

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000323

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.000249

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 3 with or without anosmia

Pathogenic:6Uncertain:1

May 20, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PS1. -

Jun 17, 2022

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PROKR2 c.58delC (p.His20MetfsX24) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 0.0001 in 251478 control chromosomes. This frequency does not allow conclusions about variant significance. c.58delC has been reported in the literature as a heterozygous genotype in individuals from a reportedly Kallman syndrome cohort (example, Sarfati_2013), idiopathic central hypogonadism (example, Libri_2014), congenital hypogonadotropic hypogonadism (example, Abbara_2021), Obesity (example, Libri_2014) and as a compound heterozygous genotype in at-least two individuals affected with hypogonadism and anosmia whose carrier mother reported as having only anosmia (example, Dode_2006). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3, Pathogenic/Likely pathogenic, n=4). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jun 24, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 06, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2 It results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein. Loss-of-function variants in PROKR2 are known to be pathogenic (PMID: 17054399). -

Mar 31, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a Likely pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with hypogonadotropic hypogonadism 3 with or without anosmia (MONDO:0009482) (PMIDs: 18826963, 29161432). (I) 0108 - This gene is associated with both recessive and dominant disease. Heterozygous, compound heterozygous and homozygous variants have been reported several times in patients with hypogonadotropic hypogonadism 3 with or without anosmia (MONDO:0009482). (I) 0112 - The condition associated with this gene has incomplete penetrance (OMIM, PMID: 18682503). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 (33 heterozygotes, 0 homozygotes). (SP) 0710 - Another NMD-predicted variant comparable to the one identified in this case has inconclusive previous evidence for pathogenicity. An individual with normosmic isolated hypogonadotropic hypogonadism was heterozygous for an NMD-predicted variant in the PROKR2 gene and also heterozygous for p.(Gln106Arg) in the GNRHR gene (PMID: 24276467). (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. It has been reported in ClinVar, four times as pathogenic/likely pathogenic and three times as VUS by clinical testing laboratories. It has been reported in DECIPHER as uncertain significance in a heterozygous individual with hypospadias. It has also been reported as heterozygous in three affected individuals (PMIDs: 23643382, 24276467), as compound heterozygous in two affected siblings (PMIDs: 17054399, 20022991), and in at least one affected individual with unknown zygosity (PMID: 23533228). In addition, the variant has been reported as heterozygous in unaffected individuals (PMID: 31589614). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

May 06, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 20, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:3

Oct 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.His20Metfs*24) in the PROKR2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PROKR2 are known to be pathogenic (PMID: 17054399, 18682503). This variant is present in population databases (rs587777834, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with Kallmann Syndrome (PMID: 17054399, 23643382, 24276467). ClinVar contains an entry for this variant (Variation ID: 3452). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PROKR2: PVS1, PS4:Moderate, PM2:Supporting -

Feb 18, 2022

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 17054399, 23643382, 29778231, 31589614, 34426522, 24276467) -

Inborn genetic diseases

Pathogenic:1

Jan 30, 2015

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected -

Hypogonadotropic hypogonadism 2 with or without anosmia

Pathogenic:1

Jan 27, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PROKR2-related disorder

Pathogenic:1

Jun 26, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PROKR2 c.58delC variant is predicted to result in a frameshift and premature protein termination (p.His20Metfs*24). This variant has been reported in the heterozygous state in several unrelated patients with Kallmann syndrome and normosmic hypogonadotropic hypogonadism (Dodé et al. 2006. PubMed ID: 17054399; referred to as p.Asp19fs in Miraoui et al. 2013. PubMed ID: 23643382, Table S3, patient 105; Libri et al. 2014. PubMed ID: 24276467). This variant has also been reported to arise de novo in a cohort of patients who performed clinical diagnostic exome sequencing (Powis et al. 2018. PubMed ID: 29778231). Of note, this variant was reported in the compound heterozygous state with a PROKR2 missense variant (c.969G>A, p.Met323Ile) in one family with Kallmann syndrome; however, the parent carrying the p.Met323Ile variant was reportedly unaffected (Family B, Dodé et al. 2006. PubMed ID: 17054399). Based on these observations, this variant is classified as pathogenic. -

not specified

Uncertain:1

Jan 21, 2020

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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