20-5302632-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP3_ModeratePP5
The NM_144773.4(PROKR2):c.563C>T(p.Ser188Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,614,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S188S) has been classified as Likely benign.
Frequency
Consequence
NM_144773.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PROKR2 | NM_144773.4 | c.563C>T | p.Ser188Leu | missense_variant | 3/3 | ENST00000678254.1 | |
PROKR2 | XM_017027646.2 | c.563C>T | p.Ser188Leu | missense_variant | 3/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PROKR2 | ENST00000678254.1 | c.563C>T | p.Ser188Leu | missense_variant | 3/3 | NM_144773.4 | P1 | ||
PROKR2 | ENST00000217270.4 | c.563C>T | p.Ser188Leu | missense_variant | 3/3 | 1 | P1 | ||
PROKR2 | ENST00000678059.1 | c.455C>T | p.Ser152Leu | missense_variant | 3/3 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152240Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251472Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135912
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461832Hom.: 0 Cov.: 46 AF XY: 0.0000165 AC XY: 12AN XY: 727206
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152358Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74510
ClinVar
Submissions by phenotype
Hypogonadotropic hypogonadism 3 with or without anosmia Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 02, 2022 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Missense changes are a common disease-causing mechanism. Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 18559922). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.52; 3Cnet: 0.88). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with PROKR2 related disorder (ClinVar ID: VCV000180158 / PMID: 18559922). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. - |
not provided Pathogenic:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 02, 2019 | This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls (PMID: 28209183, 18559922, http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant reduces the downstream signaling effects of this receptor, thus disrupting the normal function of the protein (PMID: 18559922, 29161432).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 28, 2023 | This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 188 of the PROKR2 protein (p.Ser188Leu). This variant is present in population databases (rs376239580, gnomAD 0.01%). This missense change has been observed in individual(s) with absent puberty, disorders of sex development, hypogonadotropic hypogonadism, Kallman syndrome, and/or micropenis (PMID: 18559922, 27899157, 28209183, 28754744, 31781422, 33587123, 34348883). ClinVar contains an entry for this variant (Variation ID: 180158). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PROKR2 protein function. Experimental studies have shown that this missense change affects PROKR2 function (PMID: 18559922, 24830383, 29161432, 36694982). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hypogonadotropic hypogonadism 7 with or without anosmia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | case-control | Chan Lab, Boston Children's Hospital | Nov 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at