rs78861628

chr20-5302393-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_144773.4(PROKR2):c.802C>T(p.Arg268Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00282 in 1,614,202 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R268H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.013 (52 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (56 hom.)
• Consequence: PROKR2 NM_144773.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.42

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00959307).
• BP6: Variant 20-5302393-G-A is Benign according to our data. Variant chr20-5302393-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 282345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr20-5302393-G-A is described in Lovd as [Pathogenic]. Variant chr20-5302393-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0132 (2010/152324) while in subpopulation AFR AF= 0.0453 (1885/41568). AF 95% confidence interval is 0.0436. There are 52 homozygotes in gnomad4. There are 969 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 52 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROKR2	NM_144773.4	c.802C>T	p.Arg268Cys	missense_variant	3/3	ENST00000678254.1
PROKR2	XM_017027646.2	c.802C>T	p.Arg268Cys	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROKR2	ENST00000678254.1	c.802C>T	p.Arg268Cys	missense_variant	3/3		NM_144773.4	P1
PROKR2	ENST00000217270.4	c.802C>T	p.Arg268Cys	missense_variant	3/3	1		P1
PROKR2	ENST00000678059.1	c.694C>T	p.Arg232Cys	missense_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.0132 AC: 2007 AN: 152206 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.0454

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0129

GnomAD3 exomes AF: 0.00391 AC: 983 AN: 251350 Hom.: 19 AF XY: 0.00305 AC XY: 415 AN XY: 135874

Gnomad AFR exome AF: 0.0462

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00427

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000449

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00174 AC: 2540 AN: 1461878 Hom.: 56 Cov.: 32 AF XY: 0.00154 AC XY: 1123 AN XY: 727238

Gnomad4 AFR exome AF: 0.0469

Gnomad4 AMR exome AF: 0.00335

Gnomad4 ASJ exome AF: 0.00344

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000434

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.0132 AC: 2010 AN: 152324 Hom.: 52 Cov.: 33 AF XY: 0.0130 AC XY: 969 AN XY: 74482

Gnomad4 AFR AF: 0.0453

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000338

Gnomad4 OTH AF: 0.0128

Alfa AF: 0.00399 Hom.: 10

Bravo AF: 0.0149

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0422 AC: 186

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00469 AC: 569

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 15, 2015	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 02, 2018	- -

Hypogonadotropic hypogonadism 3 with or without anosmia Benign: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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0096	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.56
MVP		0.83
ClinPred		0.020	T
GERP RS		4.1
Varity_R		0.47
gMVP		0.60

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: rs78861628; hg19: chr20-5283039; COSMIC: COSV54085211;