3-71774431-C-T

Position:

• chr3-71774431-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001126128.2(PROK2):​c.285+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,550,658 control chromosomes in the GnomAD database, including 15,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1693 hom., cov: 32)
  • Exomes 𝑓: 0.13 (14070 hom.)
• Consequence: PROK2 NM_001126128.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0410

Genes affected

PROK2 (HGNC:18455): (prokineticin 2) This gene encodes a protein expressed in the suprachiasmatic nucleus (SCN) circadian clock that may function as the output component of the circadian clock. The secreted form of the encoded protein may also serve as a chemoattractant for neuronal precursor cells in the olfactory bulb. Proteins from other vertebrates which are similar to this gene product were isolated based on homology to snake venom and secretions from frog skin, and have been shown to have diverse functions. Mutations in this gene are associated with Kallmann syndrome 4. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-71774431-C-T is Benign according to our data. Variant chr3-71774431-C-T is described in ClinVar as [Benign]. Clinvar id is 1278909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-71774431-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROK2	NM_001126128.2	c.285+14G>A		intron_variant		ENST00000295619.4	NP_001119600.1
PROK2	NM_021935.4	c.223-1603G>A		intron_variant			NP_068754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROK2	ENST00000295619.4	c.285+14G>A		intron_variant		1	NM_001126128.2	ENSP00000295619.3
PROK2	ENST00000353065.7	c.223-1603G>A		intron_variant		1		ENSP00000295618.3

Frequencies

GnomAD3 genomes AF: 0.137 AC: 20882 AN: 152024 Hom.: 1692 Cov.: 32

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.138

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.269

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.126

GnomAD3 exomes AF: 0.173 AC: 26998 AN: 156052 Hom.: 2904 AF XY: 0.181 AC XY: 15012 AN XY: 82734

Gnomad AFR exome AF: 0.129

Gnomad AMR exome AF: 0.182

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.291

Gnomad SAS exome AF: 0.320

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.129 AC: 180466 AN: 1398518 Hom.: 14070 Cov.: 32 AF XY: 0.134 AC XY: 92359 AN XY: 689782

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.173

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.316

Gnomad4 FIN exome AF: 0.172

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.137 AC: 20893 AN: 152140 Hom.: 1693 Cov.: 32 AF XY: 0.146 AC XY: 10883 AN XY: 74336

Gnomad4 AFR AF: 0.133

Gnomad4 AMR AF: 0.147

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.269

Gnomad4 SAS AF: 0.322

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.123

Alfa AF: 0.119 Hom.: 1656

Bravo AF: 0.130

Asia WGS AF: 0.249 AC: 865 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.61

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: rs3796224; hg19: chr3-71823582; COSMIC: COSV55209013;