chr3-71784983-C-A

Position:

• chr3-71784983-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• 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

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27605015).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROK2	NM_001126128.2	c.70G>T	p.Ala24Ser	missense_variant	1/4	ENST00000295619.4	NP_001119600.1
PROK2	NM_021935.4	c.70G>T	p.Ala24Ser	missense_variant	1/3		NP_068754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROK2	ENST00000295619.4	c.70G>T	p.Ala24Ser	missense_variant	1/4	1	NM_001126128.2	ENSP00000295619.3
PROK2	ENST00000353065.7	c.70G>T	p.Ala24Ser	missense_variant	1/3	1		ENSP00000295618.3

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

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

PROK2-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 30, 2024

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
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
Varity_R		0.045
gMVP		0.39

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;