20-5302137-C-T

Position:

• chr20-5302137-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5 BP4

The NM_144773.4(PROKR2):​c.1058G>A​(p.Arg353His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,614,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000068 (0 hom.)
• Consequence: PROKR2 NM_144773.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 0.508

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PP5: Variant 20-5302137-C-T is Pathogenic according to our data. Variant chr20-5302137-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1012475.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.113286436). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROKR2	NM_144773.4	c.1058G>A	p.Arg353His	missense_variant	3/3	ENST00000678254.1
PROKR2	XM_017027646.2	c.1058G>A	p.Arg353His	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROKR2	ENST00000678254.1	c.1058G>A	p.Arg353His	missense_variant	3/3		NM_144773.4	P1
PROKR2	ENST00000217270.4	c.1058G>A	p.Arg353His	missense_variant	3/3	1		P1
PROKR2	ENST00000678059.1	c.950G>A	p.Arg317His	missense_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251478 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000677 AC: 99 AN: 1461882 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000907

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.000168

Gnomad4 NFE exome AF: 0.0000423

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152262 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74466

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000579 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000741 AC: 9

EpiCase AF: 0.000327

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2022	Published functional studies demonstrate a damaging effect (Zhao et al., 2019); This variant is associated with the following publications: (PMID: 31748124, 30576231, 30602096, 34636164) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 25, 2023

Variant summary: PROKR2 c.1058G>A (p.Arg353His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251478 control chromosomes in the gnomAD database and at a frequency of 0.00068, including 72 heterozygotes and one homozygote, in the ToMMo 54KJPN dataset of East Asian control individuals. This frequency suggests the variant is not likely associated with a highly penetrant autosomal dominant condition and may be a benign polymorphism found primarily in individuals of East Asian ancestry. c.1058G>A has been reported in the literature in two Chinese individuals affected with Kallmann Syndrome 3 (Zhao_2019, Men_2020, Wang_2023). One of these individuals also had a variant in the FGFR1 gene which was suggested may contribute to the disease phenotype, possibly in an additive manner as the PROKR2 and FGFR1 variants were each inherited from an unaffected parent (Men_2020). c.1058G>A has also been reported in the heterozygous state as a VUS in an individual with nonobstructive azoospermia who did not have a clinical diagnosis of Kallmann Syndrome (Liu_2023). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found the variant had normal cell surface expression and Gas signaling, but ERK1/2 signaling and Gaq-dependent signaling was decreased to approximately 50% compared to the wild type (Zhao_2019). The following publications have been ascertained in the context of this evaluation (PMID: 36259570, 31748124, 30576231, 36694982). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Benign	0.083
Eigen_PC	Benign	0.046
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.12
Sift	Benign	0.19	T
Sift4G	Benign	0.15	T
Polyphen		0.92	P
Vest4		0.24
MVP		0.71
ClinPred		0.14	T
GERP RS		4.1
Varity_R		0.053
gMVP		0.74

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

Other links and lift over

dbSNP: rs576243101; hg19: chr20-5282783; COSMIC: COSV54085395;