chr20-5302126-G-C

Variant names:

• chr20-5302126-G-C
• rs375036628
• NM_144773.4:c.1069C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Strong

The NM_144773.4(PROKR2):​c.1069C>G​(p.Arg357Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R357W) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PROKR2 NM_144773.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.387

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.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• BP4: Computational evidence support a benign effect (MetaRNN=0.051504314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROKR2	NM_144773.4	c.1069C>G	p.Arg357Gly	missense_variant	Exon 3 of 3	ENST00000678254.1	NP_658986.1
PROKR2	XM_017027646.2	c.1069C>G	p.Arg357Gly	missense_variant	Exon 3 of 4		XP_016883135.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROKR2	ENST00000678254.1	c.1069C>G	p.Arg357Gly	missense_variant	Exon 3 of 3		NM_144773.4	ENSP00000504128.1
PROKR2	ENST00000217270.4	c.1069C>G	p.Arg357Gly	missense_variant	Exon 3 of 3	1		ENSP00000217270.3
PROKR2	ENST00000678059.1	c.961C>G	p.Arg321Gly	missense_variant	Exon 3 of 3			ENSP00000503366.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251460 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135908

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypogonadotropic hypogonadism 3 with or without anosmia Uncertain:1

Feb 12, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.91
DEOGEN2	Benign	0.10	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.95
FATHMM_MKL	Benign	0.071	N
LIST_S2	Benign	0.11	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PrimateAI	Benign	0.18	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.090
Sift	Benign	0.34	T
Sift4G	Benign	0.41	T
Polyphen		0.0	B
Vest4		0.090
MutPred		0.40		Loss of MoRF binding (P = 0.007);
MVP		0.32
ClinPred		0.030	T
GERP RS		1.7
Varity_R		0.075
gMVP		0.59

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: rs375036628; hg19: chr20-5282772;