3-71784983-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PP3_ModeratePP5

The NM_001126128.2(PROK2):c.70G>C(p.Ala24Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000012 in 1,249,706 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A24S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

PROK2
NM_001126128.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1U:1

Conservation

PhyloP100: -0.447

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 4 with or without anosmia
Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PROK2 links:

ENSG00000287131 (HGNC:58092):

ENSG00000287131 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.916

PP5

Variant 3-71784983-C-G is Pathogenic according to our data. Variant chr3-71784983-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156560.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-71784983-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156560.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-71784983-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156560.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr3-71784983-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 156560.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROK2	NM_001126128.2 link	c.70G>C	p.Ala24Pro	missense_variant	Exon 1 of 4	ENST00000295619.4	NP_001119600.1	Q9HC23-1
PROK2	NM_021935.4 link	c.70G>C	p.Ala24Pro	missense_variant	Exon 1 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.70G>C	p.Ala24Pro	missense_variant	Exon 1 of 4	1	NM_001126128.2	ENSP00000295619.3		Q9HC23-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152150

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

8052

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1097556

Hom.:

Cov.:

AF XY:

0.00000768

AC XY:

AN XY:

520986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23138

American (AMR)

AF:

0.00

AC:

AN:

8682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14462

East Asian (EAS)

AF:

0.00

AC:

AN:

26828

South Asian (SAS)

AF:

0.00

AC:

AN:

20148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4420

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

926896

Other (OTH)

AF:

0.00

AC:

AN:

44188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152150

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68006

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hypogonadotropic hypogonadism 4 with or without anosmia

Pathogenic:1

Sep 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PROK2-related disorder

Uncertain:1

Oct 27, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PROK2 c.70G>C variant is predicted to result in the amino acid substitution p.Ala24Pro. This variant was reported, along with a variant in PROKR2, in an individual with Kallmann syndrome (Cole et al. 2008. PubMed ID: 18559922; Miraoui et al. 2013. PubMed ID: 23643382). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

1.1

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.48

.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.078

LIST_S2

Benign

0.13

T;T

M_CAP

Pathogenic

0.98

MetaRNN

Pathogenic

0.92

D;D

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.3

L;L

PhyloP100

-0.45

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-1.3

N;N

REVEL

Uncertain

0.56

Sift

Benign

0.26

T;T

Sift4G

Benign

0.20

T;T

Polyphen

0.017

.;B

Vest4

0.45

MutPred

0.79

Loss of catalytic residue at A24 (P = 0.0099);Loss of catalytic residue at A24 (P = 0.0099);

MVP

0.68

MPC

0.14

ClinPred

0.11

GERP RS

-1.8

PromoterAI

-0.00040

Neutral

(source)

Varity_R

0.20

gMVP

0.52

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over