rs3746683

Variant names:

• chr20-5302670-G-C
• rs3746683
• NM_144773.4:c.525C>G

Your query was ambiguous. Multiple possible variants found:

• chr20-5302670-G-C
• chr20-5302670-G-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.525C>G​(p.Ala175Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.118 in 1,614,038 control chromosomes in the GnomAD database, including 11,930 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A175A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.12 (1111 hom., cov: 33)
  • Exomes 𝑓: 0.12 (10819 hom.)
• Consequence: PROKR2 NM_144773.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -2.96
• Publications: 11 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: ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=-0.88).
• BP6: Variant 20-5302670-G-C is Benign according to our data. Variant chr20-5302670-G-C is described in ClinVar as Benign. ClinVar VariationId is 138812.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.117 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.525C>G	p.Ala175Ala	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.525C>G	p.Ala175Ala	synonymous	Exon 3 of 3	ENSP00000504128.1	Q8NFJ6
	PROKR2	ENST00000217270.4	TSL:1	c.525C>G	p.Ala175Ala	synonymous	Exon 3 of 3	ENSP00000217270.3	Q8NFJ6
	PROKR2	ENST00000678059.1		c.417C>G	p.Ala139Ala	synonymous	Exon 3 of 3	ENSP00000503366.1	A0A7I2V3D2

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17748 AN: 152148 Hom.: 1097 Cov.: 33

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.0493

Gnomad AMR AF: 0.0807

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0352

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.115

GnomAD2 exomes AF: 0.113 AC: 28316 AN: 251430 AF XY: 0.115

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.0591

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.0322

Gnomad FIN exome AF: 0.173

Gnomad NFE exome AF: 0.122

Gnomad OTH exome AF: 0.110

GnomAD4 exome AF: 0.118 AC: 173089 AN: 1461772 Hom.: 10819 Cov.: 46 AF XY: 0.119 AC XY: 86546 AN XY: 727196

African (AFR) AF: 0.117 AC: 3919 AN: 33476

American (AMR) AF: 0.0606 AC: 2712 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.163 AC: 4261 AN: 26134

East Asian (EAS) AF: 0.0395 AC: 1569 AN: 39700

South Asian (SAS) AF: 0.126 AC: 10842 AN: 86256

European-Finnish (FIN) AF: 0.169 AC: 9029 AN: 53410

Middle Eastern (MID) AF: 0.108 AC: 624 AN: 5768

European-Non Finnish (NFE) AF: 0.119 AC: 132701 AN: 1111908

Other (OTH) AF: 0.123 AC: 7432 AN: 60396

GnomAD4 genome AF: 0.117 AC: 17788 AN: 152266 Hom.: 1111 Cov.: 33 AF XY: 0.119 AC XY: 8853 AN XY: 74450

African (AFR) AF: 0.119 AC: 4939 AN: 41542

American (AMR) AF: 0.0805 AC: 1232 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 555 AN: 3470

East Asian (EAS) AF: 0.0353 AC: 183 AN: 5180

South Asian (SAS) AF: 0.117 AC: 562 AN: 4822

European-Finnish (FIN) AF: 0.178 AC: 1883 AN: 10606

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8122 AN: 68018

Other (OTH) AF: 0.114 AC: 240 AN: 2114

Alfa AF: 0.0935 Hom.: 260

Bravo AF: 0.109

Asia WGS AF: 0.0890 AC: 310 AN: 3478

EpiCase AF: 0.127

EpiControl AF: 0.122

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.60
DANN	Benign	0.50
PhyloP100		-3.0
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: rs3746683; hg19: chr20-5283316; COSMIC: COSV54086996;