3-71772559-TAAAAA-TAAAAAAA

Variant names:

• chr3-71772559-T-TAA
• rs56679628
• NM_001126128.2:c.*163_*164dupTT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001126128.2(PROK2):​c.*163_*164dupTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 600,766 control chromosomes in the GnomAD database, including 16 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0059 (16 hom., cov: 29)
  • Exomes 𝑓: 0.0055 (0 hom.)
• Consequence: PROK2 NM_001126128.2 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0862 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.*163_*164dupTT		3_prime_UTR	Exon 4 of 4	NP_001119600.1	Q9HC23-1
	PROK2	NM_021935.4		c.*163_*164dupTT		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.*163_*164dupTT		3_prime_UTR	Exon 4 of 4	ENSP00000295619.3	Q9HC23-1
	PROK2	ENST00000353065.7	TSL:1	c.*163_*164dupTT		3_prime_UTR	Exon 3 of 3	ENSP00000295618.3	Q9HC23-2

Frequencies

GnomAD3 genomes AF: 0.00592 AC: 815 AN: 137628 Hom.: 16 Cov.: 29

Gnomad AFR AF: 0.00112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0176

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0937

Gnomad SAS AF: 0.00837

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000307

Gnomad OTH AF: 0.00903

GnomAD4 exome AF: 0.00553 AC: 2561 AN: 463070 Hom.: 0 Cov.: 0 AF XY: 0.00550 AC XY: 1349 AN XY: 245254

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

African (AFR) AF: 0.00229 AC: 28 AN: 12246

American (AMR) AF: 0.0151 AC: 252 AN: 16654

Ashkenazi Jewish (ASJ) AF: 0.00157 AC: 21 AN: 13398

East Asian (EAS) AF: 0.0512 AC: 1465 AN: 28602

South Asian (SAS) AF: 0.00515 AC: 217 AN: 42154

European-Finnish (FIN) AF: 0.00114 AC: 42 AN: 36868

Middle Eastern (MID) AF: 0.00271 AC: 6 AN: 2212

European-Non Finnish (NFE) AF: 0.00133 AC: 381 AN: 285498

Other (OTH) AF: 0.00586 AC: 149 AN: 25438

⚠️ 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: 0.00592 AC: 815 AN: 137696 Hom.: 16 Cov.: 29 AF XY: 0.00652 AC XY: 435 AN XY: 66750

African (AFR) AF: 0.00112 AC: 43 AN: 38476

American (AMR) AF: 0.0179 AC: 247 AN: 13766

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3182

East Asian (EAS) AF: 0.0933 AC: 454 AN: 4866

South Asian (SAS) AF: 0.00795 AC: 35 AN: 4404

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8156

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 276

European-Non Finnish (NFE) AF: 0.000307 AC: 19 AN: 61832

Other (OTH) AF: 0.00897 AC: 17 AN: 1896

Alfa AF: 0.00 Hom.: 6

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism

Splicing

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: COSV55209186;