NM_144773.4:c.465C>T

Variant names:

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.465C>T(p.Leu155Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,610,316 control chromosomes in the GnomAD database, including 126,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.41 ( 12642 hom., cov: 33)

Exomes 𝑓: 0.39 ( 113595 hom. )

Consequence

PROKR2
NM_144773.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.462

Publications

22 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=-0.79).

BP6

Variant 20-5302730-G-A is Benign according to our data. Variant chr20-5302730-G-A is described in ClinVar as Benign. ClinVar VariationId is 338859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.462 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROKR2	NM_144773.4 link	c.465C>T	p.Leu155Leu	synonymous_variant	Exon 3 of 3	ENST00000678254.1	NP_658986.1	Q8NFJ6A8K1T0
PROKR2	XM_017027646.2 link	c.465C>T	p.Leu155Leu	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.465C>T	p.Leu155Leu	synonymous_variant	Exon 3 of 3		NM_144773.4	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4 link	c.465C>T	p.Leu155Leu	synonymous_variant	Exon 3 of 3	1		ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1 link	c.357C>T	p.Leu119Leu	synonymous_variant	Exon 3 of 3			ENSP00000503366.1	A0A7I2V3D2

Frequencies

GnomAD3 genomes

AF:

0.406

AC:

61714

AN:

151936

Hom.:

12622

Cov.:

show subpopulations

Gnomad AFR

AF:

0.452

Gnomad AMI

AF:

0.412

Gnomad AMR

AF:

0.401

Gnomad ASJ

AF:

0.341

Gnomad EAS

AF:

0.521

Gnomad SAS

AF:

0.453

Gnomad FIN

AF:

0.328

Gnomad MID

AF:

0.396

Gnomad NFE

AF:

0.383

Gnomad OTH

AF:

0.397

GnomAD2 exomes

AF:

0.397

AC:

99358

AN:

250164

AF XY:

0.398

show subpopulations

Gnomad AFR exome

AF:

0.453

Gnomad AMR exome

AF:

0.392

Gnomad ASJ exome

AF:

0.336

Gnomad EAS exome

AF:

0.515

Gnomad FIN exome

AF:

0.335

Gnomad NFE exome

AF:

0.379

Gnomad OTH exome

AF:

0.384

GnomAD4 exome

AF:

0.392

AC:

572274

AN:

1458262

Hom.:

113595

Cov.:

AF XY:

0.393

AC XY:

285267

AN XY:

725548

show subpopulations

African (AFR)

AF:

0.447

AC:

14947

AN:

33424

American (AMR)

AF:

0.394

AC:

17611

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.338

AC:

8823

AN:

26124

East Asian (EAS)

AF:

0.484

AC:

19190

AN:

39678

South Asian (SAS)

AF:

0.433

AC:

37357

AN:

86188

European-Finnish (FIN)

AF:

0.333

AC:

17742

AN:

53246

Middle Eastern (MID)

AF:

0.422

AC:

2434

AN:

5762

European-Non Finnish (NFE)

AF:

0.388

AC:

430481

AN:

1108882

Other (OTH)

AF:

0.393

AC:

23689

AN:

60250

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

16680

33360

50039

66719

83399

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13630

27260

40890

54520

68150

<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:

0.406

AC:

61758

AN:

152054

Hom.:

12642

Cov.:

AF XY:

0.406

AC XY:

30188

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.452

AC:

18715

AN:

41448

American (AMR)

AF:

0.402

AC:

6141

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.341

AC:

1183

AN:

3466

East Asian (EAS)

AF:

0.521

AC:

2690

AN:

5164

South Asian (SAS)

AF:

0.453

AC:

2181

AN:

4816

European-Finnish (FIN)

AF:

0.328

AC:

3467

AN:

10566

Middle Eastern (MID)

AF:

0.405

AC:

119

AN:

294

European-Non Finnish (NFE)

AF:

0.383

AC:

26048

AN:

67986

Other (OTH)

AF:

0.397

AC:

838

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1886

3772

5658

7544

9430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

592

1184

1776

2368

2960

<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:

0.388

Hom.:

17130

Bravo

AF:

0.412

Asia WGS

AF:

0.422

AC:

1464

AN:

3478

EpiCase

AF:

0.382

EpiControl

AF:

0.373

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hypogonadotropic hypogonadism 3 with or without anosmia

Benign:3

Jan 13, 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. -

Jun 27, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

0.059

(source)

DANN

Benign

0.56

PhyloP100

-0.46

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