NM_144773.4:c.465C>T

Variant names:

• chr20-5302730-G-A
• rs3746684
• NM_144773.4:c.465C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_144773.4(PROKR2):​c.465C>T​(p.Leu155Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.394 in 1,610,316 control chromosomes in the GnomAD database, including 126,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (12642 hom., cov: 33)
  • Exomes 𝑓: 0.39 (113595 hom.)
• Consequence: PROKR2 NM_144773.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.462
• Publications: 22 publications found

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]

PROKR2 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 3 with or without anosmia

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Laboratory for Molecular Medicine
• hypogonadotropic hypogonadism

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Kallmann syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• septooptic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 20-5302730-G-A is Benign according to our data. Variant chr20-5302730-G-A is described in ClinVar as Benign. ClinVar VariationId is 338859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.462 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.505 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144773.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROKR2	NM_144773.4	MANE Select	c.465C>T	p.Leu155Leu	synonymous	Exon 3 of 3	NP_658986.1	Q8NFJ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROKR2	ENST00000678254.1	MANE Select	c.465C>T	p.Leu155Leu	synonymous	Exon 3 of 3	ENSP00000504128.1	Q8NFJ6
	PROKR2	ENST00000217270.4	TSL:1	c.465C>T	p.Leu155Leu	synonymous	Exon 3 of 3	ENSP00000217270.3	Q8NFJ6
	PROKR2	ENST00000678059.1		c.357C>T	p.Leu119Leu	synonymous	Exon 3 of 3	ENSP00000503366.1	A0A7I2V3D2

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61714 AN: 151936 Hom.: 12622 Cov.: 33

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.412

Gnomad AMR AF: 0.401

Gnomad ASJ AF: 0.341

Gnomad EAS AF: 0.521

Gnomad SAS AF: 0.453

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.397

GnomAD2 exomes AF: 0.397 AC: 99358 AN: 250164 AF XY: 0.398

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.392

Gnomad ASJ exome AF: 0.336

Gnomad EAS exome AF: 0.515

Gnomad FIN exome AF: 0.335

Gnomad NFE exome AF: 0.379

Gnomad OTH exome AF: 0.384

GnomAD4 exome AF: 0.392 AC: 572274 AN: 1458262 Hom.: 113595 Cov.: 36 AF XY: 0.393 AC XY: 285267 AN XY: 725548

African (AFR) AF: 0.447 AC: 14947 AN: 33424

American (AMR) AF: 0.394 AC: 17611 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 8823 AN: 26124

East Asian (EAS) AF: 0.484 AC: 19190 AN: 39678

South Asian (SAS) AF: 0.433 AC: 37357 AN: 86188

European-Finnish (FIN) AF: 0.333 AC: 17742 AN: 53246

Middle Eastern (MID) AF: 0.422 AC: 2434 AN: 5762

European-Non Finnish (NFE) AF: 0.388 AC: 430481 AN: 1108882

Other (OTH) AF: 0.393 AC: 23689 AN: 60250

GnomAD4 genome AF: 0.406 AC: 61758 AN: 152054 Hom.: 12642 Cov.: 33 AF XY: 0.406 AC XY: 30188 AN XY: 74340

African (AFR) AF: 0.452 AC: 18715 AN: 41448

American (AMR) AF: 0.402 AC: 6141 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.341 AC: 1183 AN: 3466

East Asian (EAS) AF: 0.521 AC: 2690 AN: 5164

South Asian (SAS) AF: 0.453 AC: 2181 AN: 4816

European-Finnish (FIN) AF: 0.328 AC: 3467 AN: 10566

Middle Eastern (MID) AF: 0.405 AC: 119 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26048 AN: 67986

Other (OTH) AF: 0.397 AC: 838 AN: 2110

Alfa AF: 0.388 Hom.: 17130

Bravo AF: 0.412

Asia WGS AF: 0.422 AC: 1464 AN: 3478

EpiCase AF: 0.382

EpiControl AF: 0.373

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Hypogonadotropic hypogonadism 3 with or without anosmia (3)
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.059
DANN	Benign	0.56
PhyloP100		-0.46
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3746684; hg19: chr20-5283376; COSMIC: COSV54088599;