rs121434272

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_001126128.2(PROK2):c.217C>T(p.Arg73Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000514 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

PROK2
NM_001126128.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 6.30

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 3-71781472-G-A is Pathogenic according to our data. Variant chr3-71781472-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3604.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROK2	NM_001126128.2 link	c.217C>T	p.Arg73Cys	missense_variant	Exon 2 of 4	ENST00000295619.4	NP_001119600.1	Q9HC23-1
PROK2	NM_021935.4 link	c.217C>T	p.Arg73Cys	missense_variant	Exon 2 of 3		NP_068754.1	Q9HC23-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROK2	ENST00000295619.4 link	c.217C>T	p.Arg73Cys	missense_variant	Exon 2 of 4	1	NM_001126128.2	ENSP00000295619.3		Q9HC23-1
PROK2	ENST00000353065.7 link	c.217C>T	p.Arg73Cys	missense_variant	Exon 2 of 3	1		ENSP00000295618.3		Q9HC23-2

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.000284

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000716

AC:

AN:

251420

Hom.:

AF XY:

0.0000883

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000392

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1461762

Hom.:

Cov.:

AF XY:

0.0000674

AC XY:

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000522

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000198

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000592

AC:

AN:

152074

Hom.:

Cov.:

AF XY:

0.0000808

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000284

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000659

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 4 with or without anosmia

Pathogenic:3

Dec 18, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2021

Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1Uncertain:1

Sep 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 3604). This sequence change replaces arginine with cysteine at codon 73 of the PROK2 protein (p.Arg73Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121434272, ExAC 0.02%). This missense change has been observed in individuals with clinical features of Kallman syndrome (PMID: 17054399, 18285834, 18559922, 26141714). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects PROK2 function (PMID: 18559922). 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. -

Aug 31, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported as a single heterozygous variant in patients with primary amehorrhea or Kallman syndrome; however, this variant has also been reported in unaffected relatives (PMID: 17054399, 37988663, 29298845; Ozbek et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate that this variant decreases the activity of the PROK2 protein (PMID: 18559922); This variant is associated with the following publications: (PMID: 18285834, 30024674, 17054399, 26141714, 34426522, 31589614, 19707180, 37684054, 37988663, 36700485, 23596439, 29298845, 18559922) -

PROK2-related disorder

Pathogenic:1

Jun 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PROK2 c.217C>T variant is predicted to result in the amino acid substitution p.Arg73Cys. This variant has been reported in the heterozygous, homozygous, or compound heterozygous state in patients affected with Kallmann syndrome and normosmic hypogonadotropic hypogonadism (Dodé et al. 2006. PubMed ID: 17054399; Cole et al. 2008. PubMed ID: 18559922; Leroy et al. 2008. PubMed ID: 18285834; Mao et al. 2015. PubMed ID: 26141714). This variant is expected to disrupt the formation of the disulfide bonds of the protein; in vitro functional analysis demonstrated that this variant resulted in a 7-fold decrease in calcium mobilization activity in the presence of PROK2 receptor (PROKR2) (Cole et al. 2008. PubMed ID: 18559922). This variant is reported in 0.039% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.79

.;D

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;T

M_CAP

Uncertain

0.097

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Uncertain

0.49

MutationAssessor

Benign

1.9

L;L

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

.;D

Vest4

0.54

MVP

0.99

MPC

0.58

ClinPred

0.49

GERP RS

5.7

Varity_R

0.20

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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