3-71784959-C-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5

The NM_001126128.2(PROK2):c.94G>C(p.Gly32Arg) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000617 in 1,246,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

PROK2
NM_001126128.2 missense, splice_region

Scores

Splicing: ADA: 0.5582

Clinical Significance

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

Conservation

PhyloP100: 3.80

Publications

5 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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_001126128.2

PP3

MetaRNN computational evidence supports a deleterious effect, 0.983

PP5

Variant 3-71784959-C-G is Pathogenic according to our data. Variant chr3-71784959-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 3601.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.94G>C	p.Gly32Arg	missense_variant, splice_region_variant	Exon 1 of 4	ENST00000295619.4	NP_001119600.1
PROK2	NM_021935.4 link	c.94G>C	p.Gly32Arg	missense_variant, splice_region_variant	Exon 1 of 3		NP_068754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROK2	ENST00000295619.4 link	c.94G>C	p.Gly32Arg	missense_variant, splice_region_variant	Exon 1 of 4	1	NM_001126128.2	ENSP00000295619.3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152134

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000140

AC:

AN:

7124

AF XY:

0.000288

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000366

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000649

AC:

AN:

1094834

Hom.:

Cov.:

AF XY:

0.0000712

AC XY:

AN XY:

519418

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23100

American (AMR)

AF:

0.00

AC:

AN:

8562

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14404

East Asian (EAS)

AF:

0.00

AC:

AN:

26780

South Asian (SAS)

AF:

0.00

AC:

AN:

20016

European-Finnish (FIN)

AF:

0.0000363

AC:

AN:

27520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4520

European-Non Finnish (NFE)

AF:

0.0000724

AC:

AN:

925804

Other (OTH)

AF:

0.0000680

AC:

AN:

44128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

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:

0.0000394

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41446

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68010

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.0000260

AC:

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

Oct 20, 2006

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

PROK2-related disorder

Uncertain:1

Mar 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PROK2 c.94G>C variant is predicted to result in the amino acid substitution p.Gly32Arg. This variant was reported in the heterozygous state in an individual with Kallmann syndrome (Dodé et al. 2006. PubMed ID: 17054399). This variant is reported in 0.037% of alleles in individuals of European (Non-Finnish) descent in gnomAD. 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

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.87

.;D

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.3

M;M

PhyloP100

3.8

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-5.2

D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.017

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

.;D

Vest4

0.66

MutPred

0.96

Loss of loop (P = 0.0804);Loss of loop (P = 0.0804);

MVP

0.98

MPC

0.28

ClinPred

0.84

GERP RS

4.3

PromoterAI

0.027

Neutral

(source)

Varity_R

0.77

gMVP

0.63

Mutation Taster

=45/55

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.56

dbscSNV1_RF

Benign

0.72

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over