Genetic Variant PROK2:p.Ala24Thr (chr3-71784983-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_001126128.2(PROK2):c.70G>A(p.Ala24Thr) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

PROK2
NM_001126128.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.447

Publications

3 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:

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ACMG classification

Classification was made for transcript

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=0.30452263).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROK2	NM_001126128.2 link	c.70G>A	p.Ala24Thr	missense_variant	Exon 1 of 4	ENST00000295619.4	NP_001119600.1	Q9HC23-1
PROK2	NM_021935.4 link	c.70G>A	p.Ala24Thr	missense_variant	Exon 1 of 3		NP_068754.1	Q9HC23-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROK2	ENST00000295619.4 link	c.70G>A	p.Ala24Thr	missense_variant	Exon 1 of 4	1	NM_001126128.2	ENSP00000295619.3		Q9HC23-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1097556

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

520986

African (AFR)

AF:

0.00

AC:

AN:

23138

American (AMR)

AF:

0.00

AC:

AN:

8682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14462

East Asian (EAS)

AF:

0.00

AC:

AN:

26828

South Asian (SAS)

AF:

0.00

AC:

AN:

20148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4420

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

926896

Other (OTH)

AF:

0.00

AC:

AN:

44188

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.90

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.34

.;T

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.072

LIST_S2

Benign

0.20

T;T

M_CAP

Pathogenic

0.92

MetaRNN

Benign

0.30

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.1

L;L

PhyloP100

-0.45

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.46

N;N

REVEL

Benign

0.22

Sift

Benign

0.52

T;T

Sift4G

Benign

0.41

T;T

Polyphen

0.32

.;B

Vest4

0.092

MutPred

0.40

Gain of phosphorylation at A24 (P = 0.0592);Gain of phosphorylation at A24 (P = 0.0592);

MVP

0.54

MPC

0.10

ClinPred

0.089

GERP RS

-1.8

PromoterAI

0.0074

Neutral

(source)

Varity_R

0.034

gMVP

0.41

Mutation Taster

=59/41

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over