3-71772559-TAAAAA-TAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_001126128.2(PROK2):​c.*163_*164delTT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 581,324 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0069 (11 hom., cov: 29)
  • Exomes 𝑓: 0.019 (0 hom.)
• Consequence: PROK2 NM_001126128.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.18
• 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-TAA-T is Benign according to our data. Variant chr3-71772559-TAA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1219630.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00687 (945/137590) while in subpopulation AFR AF = 0.0221 (851/38462). AF 95% confidence interval is 0.0209. There are 11 homozygotes in GnomAd4. There are 434 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 11 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.*163_*164delTT		3_prime_UTR	Exon 4 of 4	NP_001119600.1	Q9HC23-1
	PROK2	NM_021935.4		c.*163_*164delTT		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_*164delTT		3_prime_UTR	Exon 4 of 4	ENSP00000295619.3	Q9HC23-1
	PROK2	ENST00000353065.7	TSL:1	c.*163_*164delTT		3_prime_UTR	Exon 3 of 3	ENSP00000295618.3	Q9HC23-2

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 944 AN: 137526 Hom.: 11 Cov.: 29

Gnomad AFR AF: 0.0222

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00204

Gnomad ASJ AF: 0.00220

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000905

Gnomad FIN AF: 0.000617

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000696

Gnomad OTH AF: 0.00372

GnomAD4 exome AF: 0.0192 AC: 8521 AN: 443734 Hom.: 0 AF XY: 0.0187 AC XY: 4408 AN XY: 235180

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

African (AFR) AF: 0.0530 AC: 631 AN: 11906

American (AMR) AF: 0.0218 AC: 350 AN: 16024

Ashkenazi Jewish (ASJ) AF: 0.0191 AC: 244 AN: 12748

East Asian (EAS) AF: 0.0132 AC: 367 AN: 27822

South Asian (SAS) AF: 0.0120 AC: 489 AN: 40898

European-Finnish (FIN) AF: 0.0177 AC: 622 AN: 35184

Middle Eastern (MID) AF: 0.0173 AC: 37 AN: 2134

European-Non Finnish (NFE) AF: 0.0194 AC: 5289 AN: 272634

Other (OTH) AF: 0.0202 AC: 492 AN: 24384

⚠️ 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: 0.00687 AC: 945 AN: 137590 Hom.: 11 Cov.: 29 AF XY: 0.00651 AC XY: 434 AN XY: 66698

African (AFR) AF: 0.0221 AC: 851 AN: 38462

American (AMR) AF: 0.00203 AC: 28 AN: 13770

Ashkenazi Jewish (ASJ) AF: 0.00220 AC: 7 AN: 3182

East Asian (EAS) AF: 0.00 AC: 0 AN: 4868

South Asian (SAS) AF: 0.000908 AC: 4 AN: 4404

European-Finnish (FIN) AF: 0.000617 AC: 5 AN: 8108

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

European-Non Finnish (NFE) AF: 0.000696 AC: 43 AN: 61786

Other (OTH) AF: 0.00370 AC: 7 AN: 1892

Alfa AF: 0.00 Hom.: 6

ClinVar

ClinVar submissions as Germline

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
PhyloP100		1.2
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: rs56679628; hg19: chr3-71821710;