3-71774207-C-G

Variant names:

• chr3-71774207-C-G
• rs115266413
• NM_001126128.2:c.285+238G>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001126128.2(PROK2):​c.285+238G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00542 in 152,268 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0054 (10 hom., cov: 32)
• Consequence: PROK2 NM_001126128.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.140
• Publications: 0 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: SD, AD, AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-71774207-C-G is Benign according to our data. Variant chr3-71774207-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1200725.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00542 (825/152268) while in subpopulation AFR AF = 0.0191 (795/41544). AF 95% confidence interval is 0.018. There are 10 homozygotes in GnomAd4. There are 381 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,SD,AD gene

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+238G>C		intron	N/A	NP_001119600.1	Q9HC23-1
	PROK2	NM_021935.4		c.223-1379G>C		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+238G>C		intron	N/A	ENSP00000295619.3	Q9HC23-1
	PROK2	ENST00000353065.7	TSL:1	c.223-1379G>C		intron	N/A	ENSP00000295618.3	Q9HC23-2

Frequencies

GnomAD3 genomes AF: 0.00542 AC: 824 AN: 152150 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0192

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00542 AC: 825 AN: 152268 Hom.: 10 Cov.: 32 AF XY: 0.00512 AC XY: 381 AN XY: 74456

African (AFR) AF: 0.0191 AC: 795 AN: 41544

American (AMR) AF: 0.00137 AC: 21 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68020

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00430 Hom.: 0

Bravo AF: 0.00618

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.9
DANN	Benign	0.48
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

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: rs115266413; hg19: chr3-71823358;