3-71784983-C-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_001126128.2(PROK2):​c.70G>T​(p.Ala24Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A24P) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PROK2 NM_001126128.2 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: -0.447
• Publications: 3 publications found

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

ENSG00000287131 (HGNC:58092):

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.27605015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROK2	NM_001126128.2	c.70G>T	p.Ala24Ser	missense_variant	Exon 1 of 4	ENST00000295619.4	NP_001119600.1
PROK2	NM_021935.4	c.70G>T	p.Ala24Ser	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>T	p.Ala24Ser	missense_variant	Exon 1 of 4	1	NM_001126128.2	ENSP00000295619.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1097556 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 520986

African (AFR) AF: 0.00 AC: 0 AN: 23138

American (AMR) AF: 0.00 AC: 0 AN: 8682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14462

East Asian (EAS) AF: 0.00 AC: 0 AN: 26828

South Asian (SAS) AF: 0.00 AC: 0 AN: 20148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28794

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4420

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 926896

Other (OTH) AF: 0.00 AC: 0 AN: 44188

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

PROK2-related disorder Uncertain:1

Aug 30, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PROK2 c.70G>T variant is predicted to result in the amino acid substitution p.Ala24Ser. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. However, a different variant affecting this residue has been reported in patients with Kallmann syndrome (p.Ala24Pro, Cole et al. 2008. PubMed ID: 18559922, Miraoui et al. 2013. PubMed ID: 23643382). At this time, the clinical significance of the c.70G>T (p.Ala24Ser) 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	0.093
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	0.36
DANN	Benign	0.81
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.13	T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.28	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.1	L;L
PhyloP100		-0.45
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.32	N;N
REVEL	Benign	0.18
Sift	Benign	0.48	T;T
Sift4G	Benign	0.48	T;T
Polyphen		0.030	.;B
Vest4		0.063
MutPred		0.51		Gain of glycosylation at A24 (P = 0.0146);Gain of glycosylation at A24 (P = 0.0146);
MVP		0.45
MPC		0.097
ClinPred		0.085	T
GERP RS		-1.8
PromoterAI		0.017	Neutral
Varity_R		0.045
gMVP		0.39
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs587777863; hg19: chr3-71834134;