chr3-71784983-C-G

Variant names:

• chr3-71784983-C-G
• rs587777863
• NM_001126128.2:c.70G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

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
• Clinical Significance: Conflicting classifications of pathogenicity no assertion criteria provided P:1 U:1
• Conservation: PhyloP100: -0.447

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROK2	NM_001126128.2	c.70G>C	p.Ala24Pro	missense_variant	Exon 1 of 4	ENST00000295619.4	NP_001119600.1
PROK2	NM_021935.4	c.70G>C	p.Ala24Pro	missense_variant	Exon 1 of 3		NP_068754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROK2	ENST00000295619.4	c.70G>C	p.Ala24Pro	missense_variant	Exon 1 of 4	1	NM_001126128.2	ENSP00000295619.3
PROK2	ENST00000353065.7	c.70G>C	p.Ala24Pro	missense_variant	Exon 1 of 3	1		ENSP00000295618.3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32

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

GnomAD4 exome AF: 0.0000128 AC: 14 AN: 1097556 Hom.: 0 Cov.: 30 AF XY: 0.00000768 AC XY: 4 AN XY: 520986

Gnomad4 AFR exome AF: 0.00

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: 0.0000151

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152150 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: no assertion criteria provided

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	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	1.1
DANN	Benign	0.92
DEOGEN2	Uncertain	0.48	.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.078	N
LIST_S2	Benign	0.13	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.3	L;L
PrimateAI	Uncertain	0.79	T
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	T
GERP RS		-1.8
Varity_R		0.20
gMVP		0.52

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

Other links and lift over

dbSNP: rs587777863; hg19: chr3-71834134;