chr3-71774431-C-T

Variant names:

• chr3-71774431-C-T
• rs3796224
• NM_001126128.2:c.285+14G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 28 publications found

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]

PROK2 Gene-Disease associations (from GenCC):

• hypogonadotropic hypogonadism 4 with or without anosmia

  Inheritance: AR, SD, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
• hypogonadotropic hypogonadism

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1278909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001126128.2. 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
	PROK2	NM_001126128.2	MANE Select	c.285+14G>A		intron	N/A	NP_001119600.1	Q9HC23-1
	PROK2	NM_021935.4		c.223-1603G>A		intron	N/A	NP_068754.1	Q9HC23-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PROK2	ENST00000295619.4	TSL:1 MANE Select	c.285+14G>A		intron	N/A	ENSP00000295619.3	Q9HC23-1
	PROK2	ENST00000353065.7	TSL:1	c.223-1603G>A		intron	N/A	ENSP00000295618.3	Q9HC23-2

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

GnomAD2 exomes AF: 0.173 AC: 26998 AN: 156052 AF XY: 0.181

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 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

African (AFR) AF: 0.137 AC: 4316 AN: 31570

American (AMR) AF: 0.173 AC: 6161 AN: 35616

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 2637 AN: 25172

East Asian (EAS) AF: 0.226 AC: 8074 AN: 35702

South Asian (SAS) AF: 0.316 AC: 24953 AN: 79058

European-Finnish (FIN) AF: 0.172 AC: 8481 AN: 49230

Middle Eastern (MID) AF: 0.152 AC: 865 AN: 5694

European-Non Finnish (NFE) AF: 0.108 AC: 116788 AN: 1078504

Other (OTH) AF: 0.141 AC: 8191 AN: 57972

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

African (AFR) AF: 0.133 AC: 5520 AN: 41524

American (AMR) AF: 0.147 AC: 2252 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 414 AN: 3470

East Asian (EAS) AF: 0.269 AC: 1386 AN: 5160

South Asian (SAS) AF: 0.322 AC: 1547 AN: 4806

European-Finnish (FIN) AF: 0.188 AC: 1984 AN: 10566

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7359 AN: 68014

Other (OTH) AF: 0.123 AC: 261 AN: 2114

Alfa AF: 0.119 Hom.: 2190

Bravo AF: 0.130

Asia WGS AF: 0.249 AC: 865 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	3.6
DANN	Benign	0.61
PhyloP100		-0.041
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: rs3796224; hg19: chr3-71823582; COSMIC: COSV55209013;