rs3746683

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_144773.4(PROKR2):c.525C>G(p.Ala175Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,614,038 control chromosomes in the GnomAD database, including 11,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A175A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.12 ( 1111 hom., cov: 33)

Exomes 𝑓: 0.12 ( 10819 hom. )

Consequence

PROKR2
NM_144773.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -2.96

Publications

11 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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), 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

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 20-5302670-G-C is Benign according to our data. Variant chr20-5302670-G-C is described in CliVar as Benign. Clinvar id is 138812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-5302670-G-C is described in CliVar as Benign. Clinvar id is 138812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-5302670-G-C is described in CliVar as Benign. Clinvar id is 138812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-5302670-G-C is described in CliVar as Benign. Clinvar id is 138812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.96 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROKR2	NM_144773.4 link	c.525C>G	p.Ala175Ala	synonymous_variant	Exon 3 of 3	ENST00000678254.1	NP_658986.1	Q8NFJ6A8K1T0
PROKR2	XM_017027646.2 link	c.525C>G	p.Ala175Ala	synonymous_variant	Exon 3 of 4		XP_016883135.1	Q8NFJ6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
PROKR2	ENST00000678254.1 link	c.525C>G	p.Ala175Ala	synonymous_variant	Exon 3 of 3		NM_144773.4	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4 link	c.525C>G	p.Ala175Ala	synonymous_variant	Exon 3 of 3	1		ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1 link	c.417C>G	p.Ala139Ala	synonymous_variant	Exon 3 of 3			ENSP00000503366.1	A0A7I2V3D2

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17748

AN:

152148

Hom.:

1097

Cov.:

show subpopulations

Gnomad AFR

AF:

0.118

Gnomad AMI

AF:

0.0493

Gnomad AMR

AF:

0.0807

Gnomad ASJ

AF:

0.160

Gnomad EAS

AF:

0.0352

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.178

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.119

Gnomad OTH

AF:

0.115

GnomAD2 exomes

AF:

0.113

AC:

28316

AN:

251430

AF XY:

0.115

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.0591

Gnomad ASJ exome

AF:

0.157

Gnomad EAS exome

AF:

0.0322

Gnomad FIN exome

AF:

0.173

Gnomad NFE exome

AF:

0.122

Gnomad OTH exome

AF:

0.110

GnomAD4 exome

AF:

0.118

AC:

173089

AN:

1461772

Hom.:

10819

Cov.:

AF XY:

0.119

AC XY:

86546

AN XY:

727196

show subpopulations

African (AFR)

AF:

0.117

AC:

3919

AN:

33476

American (AMR)

AF:

0.0606

AC:

2712

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.163

AC:

4261

AN:

26134

East Asian (EAS)

AF:

0.0395

AC:

1569

AN:

39700

South Asian (SAS)

AF:

0.126

AC:

10842

AN:

86256

European-Finnish (FIN)

AF:

0.169

AC:

9029

AN:

53410

Middle Eastern (MID)

AF:

0.108

AC:

624

AN:

5768

European-Non Finnish (NFE)

AF:

0.119

AC:

132701

AN:

1111908

Other (OTH)

AF:

0.123

AC:

7432

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

8410

16820

25231

33641

42051

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4790

9580

14370

19160

23950

<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:

0.117

AC:

17788

AN:

152266

Hom.:

1111

Cov.:

AF XY:

0.119

AC XY:

8853

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.119

AC:

4939

AN:

41542

American (AMR)

AF:

0.0805

AC:

1232

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.160

AC:

555

AN:

3470

East Asian (EAS)

AF:

0.0353

AC:

183

AN:

5180

South Asian (SAS)

AF:

0.117

AC:

562

AN:

4822

European-Finnish (FIN)

AF:

0.178

AC:

1883

AN:

10606

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.119

AC:

8122

AN:

68018

Other (OTH)

AF:

0.114

AC:

240

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

829

1658

2486

3315

4144

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

204

408

612

816

1020

<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:

0.0935

Hom.:

260

Bravo

AF:

0.109

Asia WGS

AF:

0.0890

AC:

310

AN:

3478

EpiCase

AF:

0.127

EpiControl

AF:

0.122

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 06, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypogonadotropic hypogonadism 3 with or without anosmia

Benign:2

Jun 27, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.60

(source)

DANN

Benign

0.50

PhyloP100

-3.0

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over