3-71772816-CA-CAA

Variant names:

• chr3-71772816-C-CA
• rs768413190
• NM_001126128.2:c.297dupT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_001126128.2(PROK2):​c.297dupT​(p.Gly100TrpfsTer22) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: PROK2 NM_001126128.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:5
• Conservation: PhyloP100: -1.95

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.238 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-71772816-C-CA is Pathogenic according to our data. Variant chr3-71772816-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 420068.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=4, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PROK2	NM_001126128.2	c.297dupT	p.Gly100TrpfsTer22	frameshift_variant	Exon 4 of 4	ENST00000295619.4	NP_001119600.1
PROK2	NM_021935.4	c.234dupT	p.Gly79TrpfsTer22	frameshift_variant	Exon 3 of 3		NP_068754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PROK2	ENST00000295619.4	c.297dupT	p.Gly100TrpfsTer22	frameshift_variant	Exon 4 of 4	1	NM_001126128.2	ENSP00000295619.3
PROK2	ENST00000353065.7	c.234dupT	p.Gly79TrpfsTer22	frameshift_variant	Exon 3 of 3	1		ENSP00000295618.3

Frequencies

GnomAD3 genomes AF: 0.000178 AC: 27 AN: 152060 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.000294

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000111 AC: 28 AN: 251124 Hom.: 0 AF XY: 0.000133 AC XY: 18 AN XY: 135778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000244 AC: 356 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.000271 AC XY: 197 AN XY: 727196

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000201

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000291

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000178 AC: 27 AN: 152060 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74292

Gnomad4 AFR AF: 0.0000725

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.000479

Bravo AF: 0.000189

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hypogonadotropic hypogonadism 4 with or without anosmia Pathogenic:2 Uncertain:1

Oct 20, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PROK2 c.297dup; p.Gly100TrpfsTer22 variant (rs768413190, ClinVar Variation ID 420068), also known as p.Gly79fsTer100, is reported as both heterozygous and homozygous in individuals affected with Kallmann syndrome (Amato 2019, Dode 2006). This variant is found in the general population with an overall allele frequency of 0.01% (31/282370 alleles) in the Genome Aggregation Database (v2.1.1). This variant results in a premature termination codon in the last exon of the PROK2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated PROK2 protein. Based on available information, this variant is considered to be likely pathogenic. References: Amato LGL et al. New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism. Eur J Endocrinol. 2019 Aug 1. PMID: 31200363. Dode C et al. Kallmann syndrome: mutations in the genes encoding prokineticin-2 and prokineticin receptor-2. PLoS Genet. 2006 Oct 20. PMID: 17054399. -

Jan 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Uncertain:2

Jun 16, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported previously using alternate nomenclature (c.234_235insT) in the heterozygous state in one family with Kallmann syndrome, however, the family underwent sequencing for only two genes (Dode et al., 2006). Of the five family members heterozygous for the c.297dupT variant, one had anosmia only, another had hypogonadism only, two individuals had both hypogonadism and anosmia, and one individual was unaffected.; Frameshift variant in the C-terminus predicted to result in protein truncation, as the last 30 amino acids are lost and replaced with 21 incorrect amino acids; This variant is associated with the following publications: (PMID: 31200363, 17054399) -

Jan 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly100Trpfs*22) in the PROK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the PROK2 protein. This variant is present in population databases (rs768413190, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with clinical features of Kallmann Syndrome (PMID: 17054399, 31200363). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 420068). For these reasons, this variant has been classified as Pathogenic. -

not specified Uncertain:1

Oct 03, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: PROK2 c.297dupT (p.Gly100TrpfsX22), located in the last exon of the gene, results in a premature termination codon and is predicted to cause a truncation of the encoded protein, but is not expected to undergo nonsense mediated decay. The variant allele was found at a frequency of 0.00011 in 251124 control chromosomes (gnomAD). c.297dupT has been reported in the literature in heterozygous and homozygous individuals affected with Kallmann Syndrome/Hypogonadotropic Hypogonadism 4 With Or Without Anosmia (e.g. Dode_2006, Abreu_2008, Amato_2019). In one family with a history of anosmia, the variant was found in the heterozygous state in five individuals, two with hypogonadism and anosmia, one with only hypogonadism, one with only anosmia, and one who was unaffected (Dode_2006). In another study, the variant was found in the homozygous state in two brothers with Kallmann Syndrome, although the parents were unavailable for testing and were reportedly unaffected (Abreu_2008). In both studies, only several genes related to the phenotype were sequenced. Therefore, these reports do not provide unequivocal conclusions about association of the variant with Kallmann Syndrome/Hypogonadotropic Hypogonadism 4 With Or Without Anosmia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31200363, 17054399, 20022991, 18682503). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

PROK2-related disorder Uncertain:1

Jun 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The PROK2 c.297dupT variant is predicted to result in a frameshift and premature protein termination (p.Gly100Trpfs*22). This variant is located in the last exon of PROK2, is not predicted to undergo nonsense mediated decay, and disrupts the final ~30 amino acids. This variant, also referred to as c.234_235insT (p.Asn79fs*100), has been reported in the heterozygous state in three siblings presenting with Kallmann syndrome; it was inherited from their affected mother and was also present in an asymptomatic sister (Dodé et al. 2006. PubMed ID: 17054399, Family E). This variant has also been reported in the homozygous (Patient #6) and heterozygous (Patient #45) state in individuals with Kallmann syndrome (Amato et al. 2019. PubMed ID: 31200363). This variant is observed in 31 out of ~282,370 alleles in a large population database. This variant has conflicting interpretations of pathogenicity of uncertain and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/420068/). A premature protein termination variant (p.Arg122*) downstream of the one reported here has been reported in a patient with Kallmann syndrome (Sarfati et al. 2013. PubMed ID: 24031091). Although we suspect that this variant may be pathogenic, possibly for an autosomal recessive form of disease, the clinical significance of this variant is currently classified as uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

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

Publications

LitVar

Other links and lift over

dbSNP: rs768413190; hg19: chr3-71821967;