rs554675432

Positions:

chr3-71781525-AT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001126128.2(PROK2):c.163delA(p.Ile55fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00022 in 1,613,614 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

PROK2
NM_001126128.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 1.29

Variant links:

Genes affected

PROK2 (HGNC:18455): (prokineticin 2) This gene encodes a protein expressed in the suprachiasmatic nucleus (SCN) circadian clock that may function as the output component of the circadian clock. The secreted form of the encoded protein may also serve as a chemoattractant for neuronal precursor cells in the olfactory bulb. Proteins from other vertebrates which are similar to this gene product were isolated based on homology to snake venom and secretions from frog skin, and have been shown to have diverse functions. Mutations in this gene are associated with Kallmann syndrome 4. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

PROK2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-71781525-AT-A is Pathogenic according to our data. Variant chr3-71781525-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 3603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-71781525-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROK2	NM_001126128.2 link	c.163delA	p.Ile55fs	frameshift_variant	2/4	ENST00000295619.4	NP_001119600.1	Q9HC23-1
PROK2	NM_021935.4 link	c.163delA	p.Ile55fs	frameshift_variant	2/3		NP_068754.1	Q9HC23-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROK2	ENST00000295619.4 link	c.163delA	p.Ile55fs	frameshift_variant	2/4	1	NM_001126128.2	ENSP00000295619.3		Q9HC23-1
PROK2	ENST00000353065.7 link	c.163delA	p.Ile55fs	frameshift_variant	2/3	1		ENSP00000295618.3		Q9HC23-2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

251480

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000255

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000231

AC:

338

AN:

1461472

Hom.:

Cov.:

AF XY:

0.000221

AC XY:

161

AN XY:

727088

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000298

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000112

AC:

AN:

152142

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000347

Hom.:

Bravo

AF:

0.0000945

EpiCase

AF:

0.000491

EpiControl

AF:

0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 01, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 07, 2023	This sequence change creates a premature translational stop signal (p.Ile55*) in the PROK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PROK2 are known to be pathogenic (PMID: 17959774). This variant is present in population databases (rs554675432, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with Kallmann syndrome (PMID: 17959774, 18285834, 18559922, 23643382). It has also been observed to segregate with disease in related individuals. This variant is also known as I55fsX1. ClinVar contains an entry for this variant (Variation ID: 3603). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2023	Nonsense 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: 18559922, 18682503, 18285834, 24423319, 17959774, 29419413, 29165578, 29022642, 31200363, 31589614, 23643382, 31980526, 36268624) -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 28, 2016	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Hypogonadotropic hypogonadism 4 with or without anosmia

Pathogenic:4

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 21, 2020	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1,PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 15, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2024

The c.163delA (p.I55*) alteration, located in exon 2 (coding exon 2) of the PROK2 gene, consists of a deletion of one nucleotide at position 163. This changes the amino acid from an isoleucine (I) to a stop codon at amino acid position 55. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay; however, loss-of-function of PROK2 has not been established as a mechanism of disease for autosomal dominant PROK2-related hypogonadotropic hypogonadism with or without anosmia. for autosomal recessive PROK2-related hypogonadotropic hypogonadism with or without anosmia; however, its clinical significance for autosomal dominant PROK2-related hypogonadotropic hypogonadism with or without anosmia is uncertain. Based on data from gnomAD, the c.163delA variant has an overall frequency of 0.011% (32/282872) total alleles studied. The highest observed frequency was 0.024% (31/129182) of European (non-Finnish) alleles. This variant has been identified in the homozygous state in individual(s) with features consistent with autosomal recessive PROK2-related hypogonadotropic hypogonadism with or without anosmia (Cassatella, 2018; Pitteloud, 2007; Miraoui, 2013; Leroy, 2008; Cole, 2008). This variant has also been reported in the heterozygous state in multiple individuals with features consistent with autosomal dominant PROK2-related hypogonadotropic hypogonadism with or without anosmia (Amato, 2019; Pierzchlewska, 2017; Abreu, 2008; Cannarella, 2023). Based on the available evidence, this alteration is classified as pathogenic. -

Male infertility with azoospermia or oligozoospermia due to single gene mutation

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Sep 01, 2023

- -

PROK2-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2024

The PROK2 c.163delA variant is predicted to result in premature protein termination (p.Ile55*). This variant was reported in the homozygous state in individuals with Kallmann syndrome and hypogonadotropic hypogonadism (Pitteloud et al. 2007. PubMed ID: 17959774; Cole et al. 2008. PubMed ID: 18559922; Supplementary Table S3, Case #34, Miraoui et al. 2013. PubMed ID: 23643382). This variant has also been reported in the heterozygous state in individuals with normosmic congenital hypogonadotropic hypogonadism (ID 43 and 44, Amato et al. 2019. PubMed ID: 31200363). In vitro functional studies determined that this variant leads to loss of PROK2 activity (Pitteloud et al. 2007. PubMed ID: 17959774). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in the ClinVar database by multiple outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/3603/). Nonsense variants in PROK2 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. -

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