rs121434272

chr3-71781472-G-Achr3-71781472-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP5

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R73H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: PROK2 NM_001126128.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 6.30

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 5 ACMG points.

• PM1: In a disulfide_bond (size 62) in uniprot entity PROK2_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001126128.2
• 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: {Pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROK2	NM_001126128.2	c.217C>T	p.Arg73Cys	missense_variant	2/4	ENST00000295619.4
PROK2	NM_021935.4	c.217C>T	p.Arg73Cys	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROK2	ENST00000295619.4	c.217C>T	p.Arg73Cys	missense_variant	2/4	1	NM_001126128.2
PROK2	ENST00000353065.7	c.217C>T	p.Arg73Cys	missense_variant	2/3	1		P1

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152074 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: 0.000415

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: 18 AN: 251420 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135900

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: 74 AN: 1461762 Hom.: 0 Cov.: 30 AF XY: 0.0000674 AC XY: 49 AN XY: 727192

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: 9 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74286

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: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000659 AC: 8

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 4 with or without anosmia Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Sep 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 18, 2017	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 19, 2021

ClinVar contains an entry for this variant (Variation ID: 3604). This missense change has been observed in individuals with clinical features of Kallman syndrome (PMID: 17054399, 18285834, 18559922, 26141714). This variant is present in population databases (rs121434272, ExAC 0.02%). 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. 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. 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. Experimental studies have shown that this missense change affects PROK2 function (PMID: 18559922). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.43
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;T
M_CAP	Uncertain	0.097	D
MetaRNN	Uncertain	0.52	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	1.9	L;L
MutationTaster	Benign	1.0	A;A
PrimateAI	Benign	0.35	T
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	T
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

Other links and lift over

dbSNP: rs121434272; hg19: chr3-71830623; COSMIC: COSV55208227;