rs74315416
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Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_144773.4(PROKR2):āc.518T>Gā(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: š 0.0021 ( 1 hom., cov: 33)
Exomes š: 0.0033 ( 17 hom. )
Consequence
PROKR2
NM_144773.4 missense
NM_144773.4 missense
Scores
2
12
5
Clinical Significance
Conservation
PhyloP100: 8.78
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -8 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.061356813).
BS2
?
High Homozygotes in GnomAdExome4 at 17 AD,AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PROKR2 | NM_144773.4 | c.518T>G | p.Leu173Arg | missense_variant | 3/3 | ENST00000678254.1 | |
PROKR2 | XM_017027646.2 | c.518T>G | p.Leu173Arg | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PROKR2 | ENST00000678254.1 | c.518T>G | p.Leu173Arg | missense_variant | 3/3 | NM_144773.4 | P1 | ||
PROKR2 | ENST00000217270.4 | c.518T>G | p.Leu173Arg | missense_variant | 3/3 | 1 | P1 | ||
PROKR2 | ENST00000678059.1 | c.410T>G | p.Leu137Arg | missense_variant | 3/3 |
Frequencies
GnomAD3 genomes ? AF: 0.00212 AC: 322AN: 152244Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00230 AC: 578AN: 251442Hom.: 4 AF XY: 0.00238 AC XY: 324AN XY: 135896
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GnomAD4 exome AF: 0.00326 AC: 4772AN: 1461860Hom.: 17 Cov.: 39 AF XY: 0.00320 AC XY: 2329AN XY: 727230
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GnomAD4 genome ? AF: 0.00211 AC: 322AN: 152362Hom.: 1 Cov.: 33 AF XY: 0.00200 AC XY: 149AN XY: 74508
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:6Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:2
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | PROKR2: BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2023 | 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 (Dode et al., 2006; Caronia et al., 2011; Quaynor et al., 2011; Avbelj Stefanija et al., 2012; McCabe et al., 2013); Published functional studies demonstrate decreased signalling activity secondary to impaired cell-surface targeting of the PROKR2 receptor protein (Monnier et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22035731, 18723471, 26733480, 28754744, 18826963, 24276467, 23643382, 22466334, 23386640, 21247312, 17054399, 27168972, 22773735, 27899157, 29161432, 29419413, 34426522, 35207461, 35173048, 35236788, 33098107, 34231173, 33401665, Wang2022[case report], 33932486, 36034425, 32222824, 33988008, 36843573, 35066646, 36138264) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Dec 22, 2020 | 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. - |
Hypogonadotropic hypogonadism 3 with or without anosmia Pathogenic:1Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2009 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 02, 2022 | - - |
Infertility disorder Uncertain:1
Uncertain significance, no assertion criteria provided | provider interpretation | MAGI's Lab - Research, MAGI Group | - | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Nov 10, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at