NM_144773.4:c.518T>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_144773.4(PROKR2):c.518T>G(p.Leu173Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,614,222 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0033 ( 17 hom. )

Consequence

PROKR2
NM_144773.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:6B:5

Conservation

PhyloP100: 8.78

Publications

54 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), Ambry Genetics, ClinGen, Laboratory for Molecular Medicine
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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.061356813).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00211 (322/152362) while in subpopulation NFE AF = 0.00335 (228/68032). AF 95% confidence interval is 0.00299. There are 1 homozygotes in GnomAd4. There are 149 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 322 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.518T>G	p.Leu173Arg	missense	Exon 3 of 3	NP_658986.1	Q8NFJ6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PROKR2	ENST00000678254.1	MANE Select	c.518T>G	p.Leu173Arg	missense	Exon 3 of 3	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4	TSL:1	c.518T>G	p.Leu173Arg	missense	Exon 3 of 3	ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1		c.410T>G	p.Leu137Arg	missense	Exon 3 of 3	ENSP00000503366.1	A0A7I2V3D2

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

322

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00335

Gnomad OTH

AF:

0.000955

GnomAD2 exomes

AF:

0.00230

AC:

578

AN:

251442

AF XY:

0.00238

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00234

Gnomad ASJ exome

AF:

0.00625

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00347

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00326

AC:

4772

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00320

AC XY:

2329

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.000717

AC:

AN:

33480

American (AMR)

AF:

0.00246

AC:

110

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00517

AC:

135

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000220

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00277

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00382

AC:

4244

AN:

1111982

Other (OTH)

AF:

0.00348

AC:

210

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

250

500

751

1001

1251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

166

332

498

664

830

<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:

0.00211

AC:

322

AN:

152362

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.000986

AC:

AN:

41586

American (AMR)

AF:

0.00176

AC:

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.00634

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00335

AC:

228

AN:

68032

Other (OTH)

AF:

0.000945

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

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:

0.00307

Hom.:

Bravo

AF:

0.00232

TwinsUK

AF:

0.00539

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00349

AC:

ExAC

AF:

0.00225

AC:

273

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00463

EpiControl

AF:

0.00456

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

Hypogonadotropic hypogonadism 3 with or without anosmia (4)

not specified (2)

Hypogonadotropic hypogonadism (1)

Infertility disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.067

MetaRNN

Benign

0.061

MetaSVM

Benign

-0.58

MutationAssessor

Uncertain

2.6

PhyloP100

8.8

PrimateAI

Uncertain

0.70

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.56

Sift

Uncertain

0.0060

Sift4G

Uncertain

0.027

Polyphen

0.99

Vest4

0.93

MVP

0.75

ClinPred

0.033

GERP RS

5.2

Varity_R

0.78

gMVP

0.81

Mutation Taster

=28/72

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over