rs74315416

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM1BP4_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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM1

In a disulfide_bond (size 80) in uniprot entity PKR2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_144773.4

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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROKR2	NM_144773.4 link	c.518T>G	p.Leu173Arg	missense_variant	Exon 3 of 3	ENST00000678254.1	NP_658986.1	Q8NFJ6A8K1T0
PROKR2	XM_017027646.2 link	c.518T>G	p.Leu173Arg	missense_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.518T>G	p.Leu173Arg	missense_variant	Exon 3 of 3		NM_144773.4	ENSP00000504128.1	Q8NFJ6
PROKR2	ENST00000217270.4 link	c.518T>G	p.Leu173Arg	missense_variant	Exon 3 of 3	1		ENSP00000217270.3	Q8NFJ6
PROKR2	ENST00000678059.1 link	c.410T>G	p.Leu137Arg	missense_variant	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

GnomAD3 exomes

AF:

0.00230

AC:

578

AN:

251442

Hom.:

AF XY:

0.00238

AC XY:

324

AN XY:

135896

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 SAS exome

AF:

0.000294

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

Gnomad4 AFR exome

AF:

0.000717

Gnomad4 AMR exome

AF:

0.00246

Gnomad4 ASJ exome

AF:

0.00517

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.000262

Gnomad4 NFE exome

AF:

0.00382

Gnomad4 OTH exome

AF:

0.00348

GnomAD4 genome

AF:

0.00211

AC:

322

AN:

152362

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

149

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00335

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.00325

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:6Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PROKR2 p.Leu173Arg variant was identified in several compound heterozygous and homozygous individuals with idiopathic central hypogonadism, as well as a four heterozygous individuals with complex congenital hypopituitarism (Stefanija_2012_PMID:22773735; McCabe_2013_PMID:23386640; Dode_2006_PMID: 17054399; Cole_2008_PMID:18559922). Pathogenic variants in the PROKR2 gene have been reported to associate with the autosomal recessive form of isolated gondotropin-releasing hormone (GnRH) deficiency. In familial cases, this variant is shown to segregate with disease. However, this variant is also seen in unaffected homozygous and heterozygous individuals, which is inconsistent with the autosomal recessive form of GnRH deficiency (McCabe_2013_PMID:23386640; Dode_2006_PMID: 17054399). The variant was identified in dbSNP (ID: rs74315416), LOVD 3.0 and ClinVar (classified as likely benign by Invitae, Illumina and Division of Genomic Diagnostics, Children's Hospital of Philadelphia, as uncertain significance by GeneDx and Mendelics, and as pathogenic by Athena Diagnostics). The variant was identified in control databases in 621 of 282842 chromosomes (4 homozygous) at a frequency of 0.002196 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Ashkenazi Jewish in 65 of 10370 chromosomes (freq: 0.006268), European (non-Finnish) in 429 of 129164 chromosomes (freq: 0.003321), Latino in 81 of 35436 chromosomes (freq: 0.002286), Other in 15 of 7222 chromosomes (freq: 0.002077), African in 21 of 24964 chromosomes (freq: 0.000841), South Asian in 9 of 30616 chromosomes (freq: 0.000294) and European (Finnish) in 1 of 25118 chromosomes (freq: 0.00004), but was not observed in the East Asian population. The p.Leu173 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies reveal that this variant causes impaired protein activity by affecting normal protein localization to the cell surface (Libri_2014_PMID:24276467; Monnier_2009_PMID:18826963; Cole_2008_PMID:18559922). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 22, 2020

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The best available variant frequency is higher than the disease allele frequency; however, this variant is statistically enriched in patients compared to population databases. Variant has been seen homozygously in unaffected individuals. Assessment of experimental evidence suggests this variant results in abnormal protein function. -

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PROKR2: BS1, BS2 -

Sep 23, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the heterozygous, homozygous, or compound heterozygous state in published literature in multiple unrelated patients from different ethnic backgrounds with variable phenotypes, including classic Kallman syndrome with anosmia and hypogonadism, hypogonadotropic hypogonadism, hypothalamic amenorrhea, and gonadotropin-releasing hormone (GnRH) deficiency (PMID: 17054399, 21247312, 22035731, 22773735, 23386640); Published functional studies demonstrate decreased signalling activity secondary to impaired cell-surface targeting of the PROKR2 receptor protein (PMID: 18826963); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22035731, 18723471, 26733480, 28754744, 24276467, 23643382, 22466334, 23386640, 21247312, 27168972, 27899157, 29161432, 29419413, 34426522, 35207461, 35173048, 35236788, 33098107, 34231173, 33401665, Wang2022[case report], 33932486, 36531499, 30476936, 36034425, 32222824, 33988008, 36843573, 35066646, 36138264, 36920900, 25071724, 37338295, 37321569, 36694982, 18826963, 22773735, 17054399) -

Hypogonadotropic hypogonadism 3 with or without anosmia

Pathogenic:1Uncertain:2Benign:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 02, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Benign:2

Jun 11, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 10, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypogonadotropic hypogonadism

Pathogenic:1

Nov 11, 2024

NHS Central & South Genomic Laboratory Hub

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infertility disorder

Uncertain:1

MAGI's Lab - Research, MAGI Group

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.077

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over