3-71772559-TAAAAA-TAAAAAA

Variant names:

• chr3-71772559-T-TA
• rs56679628
• NM_001126128.2:c.*164dupT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001126128.2(PROK2):​c.*164dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.105 in 596,012 control chromosomes in the GnomAD database, including 1,002 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (991 hom., cov: 29)
  • Exomes 𝑓: 0.10 (11 hom.)
• Consequence: PROK2 NM_001126128.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.92
• 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: 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 -10 ACMG points.

• BP6: Variant 3-71772559-T-TA is Benign according to our data. Variant chr3-71772559-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1239728.Status of the report is criteria_provided_single_submitter, 1 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.*164dupT		3_prime_UTR	Exon 4 of 4	NP_001119600.1	Q9HC23-1
	PROK2	NM_021935.4		c.*164dupT		3_prime_UTR	Exon 3 of 3	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.*164dupT		3_prime_UTR	Exon 4 of 4	ENSP00000295619.3	Q9HC23-1
	PROK2	ENST00000353065.7	TSL:1	c.*164dupT		3_prime_UTR	Exon 3 of 3	ENSP00000295618.3	Q9HC23-2

Frequencies

GnomAD3 genomes AF: 0.108 AC: 14894 AN: 137528 Hom.: 989 Cov.: 29

Gnomad AFR AF: 0.133

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.122

Gnomad ASJ AF: 0.0930

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.321

Gnomad FIN AF: 0.0712

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.0728

Gnomad OTH AF: 0.0974

GnomAD4 exome AF: 0.103 AC: 47402 AN: 458416 Hom.: 11 Cov.: 0 AF XY: 0.109 AC XY: 26413 AN XY: 242680

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.110 AC: 1330 AN: 12124

American (AMR) AF: 0.113 AC: 1871 AN: 16550

Ashkenazi Jewish (ASJ) AF: 0.0881 AC: 1164 AN: 13216

East Asian (EAS) AF: 0.167 AC: 4750 AN: 28460

South Asian (SAS) AF: 0.219 AC: 9118 AN: 41668

European-Finnish (FIN) AF: 0.0708 AC: 2582 AN: 36462

Middle Eastern (MID) AF: 0.125 AC: 274 AN: 2196

European-Non Finnish (NFE) AF: 0.0837 AC: 23665 AN: 282582

Other (OTH) AF: 0.105 AC: 2648 AN: 25158

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.108 AC: 14902 AN: 137596 Hom.: 991 Cov.: 29 AF XY: 0.116 AC XY: 7709 AN XY: 66712

African (AFR) AF: 0.133 AC: 5094 AN: 38444

American (AMR) AF: 0.122 AC: 1675 AN: 13764

Ashkenazi Jewish (ASJ) AF: 0.0930 AC: 296 AN: 3182

East Asian (EAS) AF: 0.213 AC: 1035 AN: 4864

South Asian (SAS) AF: 0.323 AC: 1419 AN: 4400

European-Finnish (FIN) AF: 0.0712 AC: 579 AN: 8132

Middle Eastern (MID) AF: 0.141 AC: 39 AN: 276

European-Non Finnish (NFE) AF: 0.0728 AC: 4496 AN: 61800

Other (OTH) AF: 0.0951 AC: 180 AN: 1892

Alfa AF: 0.0125 Hom.: 6

ClinVar

ClinVar submissions as Germline

Significance: 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
PhyloP100		-1.9
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: rs56679628; hg19: chr3-71821710; COSMIC: COSV55209269;