Genetic Variant NM_001126128.2:c.70G>T (chr3-71784983-C-A) – 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>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

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

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: SD, AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
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 ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 156560.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.27605015).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126128.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROK2	NM_001126128.2	MANE Select	c.70G>T	p.Ala24Ser	missense	Exon 1 of 4	NP_001119600.1	Q9HC23-1
	PROK2	NM_021935.4		c.70G>T	p.Ala24Ser	missense	Exon 1 of 3	NP_068754.1	Q9HC23-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PROK2	ENST00000295619.4	TSL:1 MANE Select	c.70G>T	p.Ala24Ser	missense	Exon 1 of 4	ENSP00000295619.3	Q9HC23-1
PROK2	ENST00000353065.7	TSL:1	c.70G>T	p.Ala24Ser	missense	Exon 1 of 3	ENSP00000295618.3	Q9HC23-2
ENSG00000287131	ENST00000725818.1		n.243+291C>A		intron	N/A

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.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

PROK2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

0.36

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.34

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.13

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.1

PhyloP100

-0.45

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.32

REVEL

Benign

0.18

Sift

Benign

0.48

Sift4G

Benign

0.48

Polyphen

0.030

Vest4

0.063

MutPred

0.51

Gain of glycosylation at A24 (P = 0.0146)

MVP

0.45

MPC

0.097

ClinPred

0.085

GERP RS

-1.8

PromoterAI

0.017

Neutral

(source)

Varity_R

0.045

gMVP

0.39

Mutation Taster

=86/14

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over