rs144994507

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_144773.4(PROKR2):c.151G>A(p.Ala51Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,614,074 control chromosomes in the GnomAD database, including 28 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A51A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0032 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0022 ( 25 hom. )

Consequence

PROKR2
NM_144773.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 2.17

Publications

17 publications found

Variant links:

Genes affected

PROKR2 (HGNC:15836): (prokineticin receptor 2) Prokineticins are secreted proteins that can promote angiogenesis and induce strong gastrointestinal smooth muscle contraction. The protein encoded by this gene is an integral membrane protein and G protein-coupled receptor for prokineticins. The encoded protein is similar in sequence to GPR73, another G protein-coupled receptor for prokineticins. [provided by RefSeq, Jul 2008]

PROKR2 Gene-Disease associations (from GenCC):

hypogonadotropic hypogonadism 3 with or without anosmia
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Ambry Genetics
hypogonadotropic hypogonadism
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Kallmann syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
septooptic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PROKR2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_144773.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0076317787).

BP6

Variant 20-5314219-C-T is Benign according to our data. Variant chr20-5314219-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 338865.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00316 (481/152192) while in subpopulation EAS AF = 0.0158 (82/5180). AF 95% confidence interval is 0.0131. There are 3 homozygotes in GnomAd4. There are 310 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 481 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144773.4. 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
	PROKR2	NM_144773.4	MANE Select	c.151G>A	p.Ala51Thr	missense	Exon 2 of 3	NP_658986.1	Q8NFJ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PROKR2	ENST00000678254.1	MANE Select	c.151G>A	p.Ala51Thr	missense	Exon 2 of 3	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4	TSL:1	c.151G>A	p.Ala51Thr	missense	Exon 2 of 3	ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1		c.43G>A	p.Ala15Thr	missense	Exon 2 of 3	ENSP00000503366.1	A0A7I2V3D2

Frequencies

GnomAD3 genomes

AF:

0.00316

AC:

481

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0158

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0227

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00197

Gnomad OTH

AF:

0.00192

GnomAD2 exomes

AF:

0.00449

AC:

1129

AN:

251486

AF XY:

0.00425

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0195

Gnomad FIN exome

AF:

0.0210

Gnomad NFE exome

AF:

0.00222

Gnomad OTH exome

AF:

0.00293

GnomAD4 exome

AF:

0.00216

AC:

3158

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00214

AC XY:

1558

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00907

AC:

360

AN:

39700

South Asian (SAS)

AF:

0.00124

AC:

107

AN:

86256

European-Finnish (FIN)

AF:

0.0196

AC:

1045

AN:

53420

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00133

AC:

1478

AN:

1112002

Other (OTH)

AF:

0.00245

AC:

148

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

227

453

680

906

1133

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00316

AC:

481

AN:

152192

Hom.:

Cov.:

AF XY:

0.00417

AC XY:

310

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41520

American (AMR)

AF:

0.000261

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.0158

AC:

AN:

5180

South Asian (SAS)

AF:

0.00124

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.0227

AC:

240

AN:

10578

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00197

AC:

134

AN:

68004

Other (OTH)

AF:

0.00190

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00176

Hom.:

Bravo

AF:

0.00110

Asia WGS

AF:

0.00375

AC:

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00124

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

Hypogonadotropic hypogonadism 3 with or without anosmia (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.093

Eigen

Benign

-0.092

Eigen_PC

Benign

0.032

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.88

MetaRNN

Benign

0.0076

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

2.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.84

REVEL

Benign

0.088

Sift

Benign

0.14

Sift4G

Benign

0.29

Varity_R

0.13

gMVP

0.50

Mutation Taster

=83/17

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over