rs796052865
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PM4
The NM_007254.4(PNKP):βc.1074_1085delβ(p.Arg358_Leu361del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000131 in 152,150 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ). Synonymous variant affecting the same amino acid position (i.e. R358R) has been classified as Likely benign.
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 32)
Consequence
PNKP
NM_007254.4 inframe_deletion
NM_007254.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.06
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_007254.4.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PNKP | NM_007254.4 | c.1074_1085del | p.Arg358_Leu361del | inframe_deletion | 12/17 | ENST00000322344.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PNKP | ENST00000322344.8 | c.1074_1085del | p.Arg358_Leu361del | inframe_deletion | 12/17 | 1 | NM_007254.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32
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We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74328
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2014 | A variant of unknown significance has been identified in the PNKP gene. The c.1074_1085delGGCCCTCCTGAG variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.1074_1085delGGCCCTCCTGAG variant results in an in-frame deletion of four amino acid residues, denoted p.R358_L361del, and is not expected to result in protein truncation or nonsense-mediated mRNA decay. This deletion occurs at a position that is not conserved across species, and in-frame deletions have not been reported in the PNKP gene in association with PNKP-related disorders. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in RETT-EPI panel(s). - |
Developmental and epileptic encephalopathy, 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 09, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 206434). This variant has not been reported in the literature in individuals affected with PNKP-related conditions. This variant is not present in population databases (gnomAD no frequency). This variant, c.1074_1085del, results in the deletion of 4 amino acid(s) of the PNKP protein (p.Arg358_Leu361del), but otherwise preserves the integrity of the reading frame. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at