3-71772559-TAAAAA-TAAAA

Variant names:

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

Variant summary

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

The NM_001126128.2(PROK2):​c.*164delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.253 in 564,984 control chromosomes in the GnomAD database, including 590 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.061 (585 hom., cov: 29)
  • Exomes 𝑓: 0.32 (5 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-TA-T is Benign according to our data. Variant chr3-71772559-TA-T is described in ClinVar as Benign. ClinVar VariationId is 1220791.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 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.*164delT		3_prime_UTR	Exon 4 of 4	NP_001119600.1	Q9HC23-1
	PROK2	NM_021935.4		c.*164delT		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.*164delT		3_prime_UTR	Exon 4 of 4	ENSP00000295619.3	Q9HC23-1
	PROK2	ENST00000353065.7	TSL:1	c.*164delT		3_prime_UTR	Exon 3 of 3	ENSP00000295618.3	Q9HC23-2

Frequencies

GnomAD3 genomes AF: 0.0606 AC: 8306 AN: 137160 Hom.: 579 Cov.: 29

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.0309

Gnomad AMR AF: 0.0271

Gnomad ASJ AF: 0.00221

Gnomad EAS AF: 0.00349

Gnomad SAS AF: 0.00385

Gnomad FIN AF: 0.0278

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.00753

Gnomad OTH AF: 0.0479

GnomAD4 exome AF: 0.315 AC: 134806 AN: 427760 Hom.: 5 Cov.: 0 AF XY: 0.312 AC XY: 70674 AN XY: 226792

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

African (AFR) AF: 0.347 AC: 4062 AN: 11692

American (AMR) AF: 0.309 AC: 4812 AN: 15554

Ashkenazi Jewish (ASJ) AF: 0.327 AC: 4020 AN: 12310

East Asian (EAS) AF: 0.239 AC: 6466 AN: 27014

South Asian (SAS) AF: 0.237 AC: 9378 AN: 39528

European-Finnish (FIN) AF: 0.332 AC: 11310 AN: 34080

Middle Eastern (MID) AF: 0.273 AC: 562 AN: 2062

European-Non Finnish (NFE) AF: 0.331 AC: 86763 AN: 262076

Other (OTH) AF: 0.317 AC: 7433 AN: 23444

⚠️ 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: 0.0608 AC: 8340 AN: 137224 Hom.: 585 Cov.: 29 AF XY: 0.0600 AC XY: 3989 AN XY: 66476

African (AFR) AF: 0.185 AC: 7121 AN: 38424

American (AMR) AF: 0.0271 AC: 372 AN: 13728

Ashkenazi Jewish (ASJ) AF: 0.00221 AC: 7 AN: 3170

East Asian (EAS) AF: 0.00370 AC: 18 AN: 4862

South Asian (SAS) AF: 0.00364 AC: 16 AN: 4400

European-Finnish (FIN) AF: 0.0278 AC: 222 AN: 7980

Middle Eastern (MID) AF: 0.0109 AC: 3 AN: 276

European-Non Finnish (NFE) AF: 0.00753 AC: 464 AN: 61648

Other (OTH) AF: 0.0480 AC: 91 AN: 1894

Alfa AF: 0.000459 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: COSV55208625;