19-49865209-C-T
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_007254.4(PNKP):c.416G>A(p.Arg139His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00292 in 1,614,214 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_007254.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PNKP | NM_007254.4 | c.416G>A | p.Arg139His | missense_variant | 4/17 | ENST00000322344.8 | NP_009185.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PNKP | ENST00000322344.8 | c.416G>A | p.Arg139His | missense_variant | 4/17 | 1 | NM_007254.4 | ENSP00000323511.2 |
Frequencies
GnomAD3 genomes AF: 0.00182 AC: 277AN: 152228Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00194 AC: 487AN: 251392Hom.: 2 AF XY: 0.00218 AC XY: 296AN XY: 135896
GnomAD4 exome AF: 0.00304 AC: 4437AN: 1461868Hom.: 7 Cov.: 34 AF XY: 0.00295 AC XY: 2148AN XY: 727236
GnomAD4 genome AF: 0.00182 AC: 277AN: 152346Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122AN XY: 74498
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | PNKP: BP4, BS2 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 14, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 28, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 15, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Apr 15, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 24, 2018 | - - |
Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Oct 24, 2018 | PNKP NM_007254.3 exon 4 p.Arg139His (c.416G>A): This variant has not been reported in the literature and is present in 0.3% (379/126666) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-50368466-C-T). This variant is present in ClinVar (Variation ID:159794). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 23, 2017 | - - |
Microcephaly, seizures, and developmental delay Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Uncertain significance, no assertion criteria provided | research | Division of Human Genetics, Children's Hospital of Philadelphia | Dec 12, 2014 | The heterozygous variant (c.416G>A; p.Arg139His) in the PNKP gene observed in this patient has not been associated with disease. It occurs at low frequencies in control population (0.2% in ExAC) and a second rare variant was not observed on the other allele. This variant is considered a variant of unknown significance. - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 13, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 10, 2023 | Variant summary: PNKP c.416G>A (p.Arg139His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0019 in 251392 control chromosomes in the gnomAD database, including 2 homozygotes. To our knowledge, c.416G>A has not been reported in the literature in individuals affected with PNKP-Related Disorders and 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: 23833122, 34009545). 13 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS (n=6), likely benign (n=6), benign (n=1)). Based on the evidence outlined above, the variant was classified as likely benign. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 08, 2019 | The p.R139H variant (also known as c.416G>A), located in coding exon 3 of the PNKP gene, results from a G to A substitution at nucleotide position 416. The arginine at codon 139 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
PNKP-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 27, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Charcot-Marie-Tooth disease type 2B2;C3150667:Microcephaly, seizures, and developmental delay;C4225397:Ataxia - oculomotor apraxia type 4 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Nov 11, 2021 | PNKP NM_007254.3 exon 4 p.Arg139His (c.416G>A): This variant has not been reported in the literature and is present in 0.3% (379/126666) of European alleles, including 2 homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-50368466-C-T). This variant is present in ClinVar (Variation ID:159794). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. - |
Developmental and epileptic encephalopathy, 12 Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at