rs74315419

Positions:

• chr20-5302226-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_144773.4(PROKR2):​c.969G>A​(p.Met323Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PROKR2 NM_144773.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.43

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 20-5302226-C-T is Pathogenic according to our data. Variant chr20-5302226-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 3453.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PROKR2	NM_144773.4	c.969G>A	p.Met323Ile	missense_variant	3/3	ENST00000678254.1
PROKR2	XM_017027646.2	c.969G>A	p.Met323Ile	missense_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PROKR2	ENST00000678254.1	c.969G>A	p.Met323Ile	missense_variant	3/3		NM_144773.4	P1
PROKR2	ENST00000217270.4	c.969G>A	p.Met323Ile	missense_variant	3/3	1		P1
PROKR2	ENST00000678059.1	c.861G>A	p.Met287Ile	missense_variant	3/3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Hypogonadotropic hypogonadism 3 with or without anosmia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 20, 2006

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.72
Sift	Benign	0.080	T
Sift4G	Benign	0.069	T
Polyphen		0.84	P
Vest4		0.94
MutPred		0.93		Gain of catalytic residue at M323 (P = 0.1183);
MVP		0.84
ClinPred		0.98	D
GERP RS		5.0
Varity_R		0.66
gMVP		0.67

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: rs74315419; hg19: chr20-5282872;