19-49861233-G-A
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_007254.4(PNKP):c.*15C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,505,468 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0056 ( 5 hom., cov: 32)
Exomes 𝑓: 0.00054 ( 11 hom. )
Consequence
PNKP
NM_007254.4 3_prime_UTR
NM_007254.4 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.517
Genes affected
PNKP (HGNC:9154): (polynucleotide kinase 3'-phosphatase) This locus represents a gene involved in DNA repair. In response to ionizing radiation or oxidative damage, the protein encoded by this locus catalyzes 5' phosphorylation and 3' dephosphorylation of nucleic acids. Mutations at this locus have been associated with microcephaly, seizures, and developmental delay.[provided by RefSeq, Sep 2010]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.77).
BP6
Variant 19-49861233-G-A is Benign according to our data. Variant chr19-49861233-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138727.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=2, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00559 (852/152316) while in subpopulation AFR AF= 0.0197 (821/41570). AF 95% confidence interval is 0.0186. There are 5 homozygotes in gnomad4. There are 371 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 5 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PNKP | NM_007254.4 | c.*15C>T | 3_prime_UTR_variant | 17/17 | ENST00000322344.8 | NP_009185.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PNKP | ENST00000322344.8 | c.*15C>T | 3_prime_UTR_variant | 17/17 | 1 | NM_007254.4 | ENSP00000323511 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00558 AC: 849AN: 152198Hom.: 5 Cov.: 32
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GnomAD3 exomes AF: 0.00134 AC: 333AN: 249132Hom.: 5 AF XY: 0.000924 AC XY: 125AN XY: 135234
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GnomAD4 exome AF: 0.000537 AC: 726AN: 1353152Hom.: 11 Cov.: 21 AF XY: 0.000423 AC XY: 287AN XY: 678854
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GnomAD4 genome AF: 0.00559 AC: 852AN: 152316Hom.: 5 Cov.: 32 AF XY: 0.00498 AC XY: 371AN XY: 74490
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Microcephaly, seizures, and developmental delay Uncertain:1Benign:1
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Feb 08, 2013 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 12, 2012 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Inborn genetic diseases Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 30, 2017 | This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at