rs144994507

Positions:

• chr20-5314219-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_144773.4(PROKR2):​c.151G>A​(p.Ala51Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,614,074 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.0032 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (25 hom.)
• Consequence: PROKR2 NM_144773.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 2.17

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0076317787).
• BP6: Variant 20-5314219-C-T is Benign according to our data. Variant chr20-5314219-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 338865.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. Variant chr20-5314219-C-T is described in Lovd as [Benign]. Variant chr20-5314219-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00316 (481/152192) while in subpopulation EAS AF= 0.0158 (82/5180). AF 95% confidence interval is 0.0131. There are 3 homozygotes in gnomad4. There are 310 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROKR2	NM_144773.4	c.151G>A	p.Ala51Thr	missense_variant	2/3	ENST00000678254.1	NP_658986.1
PROKR2	XM_017027646.2	c.151G>A	p.Ala51Thr	missense_variant	2/4		XP_016883135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROKR2	ENST00000678254.1	c.151G>A	p.Ala51Thr	missense_variant	2/3		NM_144773.4	ENSP00000504128.1
PROKR2	ENST00000217270.4	c.151G>A	p.Ala51Thr	missense_variant	2/3	1		ENSP00000217270.3
PROKR2	ENST00000678059.1	c.43G>A	p.Ala15Thr	missense_variant	2/3			ENSP00000503366.1

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152074 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000266

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0227

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.00192

GnomAD3 exomes AF: 0.00449 AC: 1129 AN: 251486 Hom.: 15 AF XY: 0.00425 AC XY: 577 AN XY: 135914

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0195

Gnomad SAS exome AF: 0.00124

Gnomad FIN exome AF: 0.0210

Gnomad NFE exome AF: 0.00222

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00216 AC: 3158 AN: 1461882 Hom.: 25 Cov.: 34 AF XY: 0.00214 AC XY: 1558 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00907

Gnomad4 SAS exome AF: 0.00124

Gnomad4 FIN exome AF: 0.0196

Gnomad4 NFE exome AF: 0.00133

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00316 AC: 481 AN: 152192 Hom.: 3 Cov.: 32 AF XY: 0.00417 AC XY: 310 AN XY: 74418

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0158

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0227

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.00190

Alfa AF: 0.00164 Hom.: 1

Bravo AF: 0.00110

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.00419 AC: 509

Asia WGS AF: 0.00375 AC: 14 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00124

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	PROKR2: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 30, 2015

Lines of evidence used in support of classification: CANDIDATE: Alteration(s) of Potential Clinical Relevance Detected -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Hypogonadotropic hypogonadism 3 with or without anosmia Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.092
Eigen_PC	Benign	0.032
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.088
Sift	Benign	0.14	T
Sift4G	Benign	0.29	T
Polyphen		0.027	B
Vest4		0.29
MVP		0.58
ClinPred		0.013	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.50

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: rs144994507; hg19: chr20-5294865; COSMIC: COSV54087829;