rs786205207
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PM4_SupportingPP5_Very_Strong
The NM_007254.4(PNKP):c.1221_1223delCAC(p.Thr408del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000289 in 1,593,860 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_007254.4 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000224 AC: 34AN: 152110Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000683 AC: 15AN: 219494Hom.: 0 AF XY: 0.0000754 AC XY: 9AN XY: 119352
GnomAD4 exome AF: 0.00000832 AC: 12AN: 1441750Hom.: 0 AF XY: 0.00000977 AC XY: 7AN XY: 716466
GnomAD4 genome AF: 0.000224 AC: 34AN: 152110Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21AN XY: 74312
ClinVar
Submissions by phenotype
Charcot-Marie-Tooth disease type 2B2 Pathogenic:2
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The variant p.Thr408Del variant in the PNKP gene has been observed in patients with CMT2B2 and ataxia with oculomotor apraxia type 4. ClinVar classifies this variant as Pathogenic (Variation ID: 190219), 2 stars (multiple consistent, 6 submissions), citing 3 articles (30039206, 27066567 and 25728773). This variant is present in heterozygous in 15 alleles in the GnomAD database and absents in the ABraOM database. This variant deletes one amino acid of the PNKP protein, which is highly conserved across different species. This variant is in an important functional domain of the protein (Kinase). In summary, the p.Thr408Del meets our criteria to be classified as pathogenic. -
Ataxia - oculomotor apraxia type 4 Pathogenic:2
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Microcephaly, seizures, and developmental delay Pathogenic:1
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not provided Pathogenic:1
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Developmental and epileptic encephalopathy, 12 Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this variant affects PNKP function (PMID: 27066567). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 190219). This variant has been observed in individual(s) with PNKP-related conditions (PMID: 25728773, 27066567, 30039206; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs786205207, gnomAD 0.05%). This variant, c.1221_1223del, results in the deletion of 1 amino acid(s) of the PNKP protein (p.Thr408del), but otherwise preserves the integrity of the reading frame. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at