1-33013198-AGTCTT-TGAGTTTATGTTTATGTTTATGAGTC
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP3
The ENST00000373449.7(AK2):c.694+4_694+9delinsGACTCATAAACATAAACATAAACTCA variant causes a splice donor, splice donor region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
AK2
ENST00000373449.7 splice_donor, splice_donor_region, intron
ENST00000373449.7 splice_donor, splice_donor_region, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.93
Genes affected
AK2 (HGNC:362): (adenylate kinase 2) Adenylate kinases are involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of phosphate groups among adenine nucleotides. Three isozymes of adenylate kinase, namely 1, 2, and 3, have been identified in vertebrates; this gene encodes isozyme 2. Expression of these isozymes is tissue-specific and developmentally regulated. Isozyme 2 is localized in the mitochondrial intermembrane space and may play a role in apoptosis. Mutations in this gene are the cause of reticular dysgenesis. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 1 and 2.[provided by RefSeq, Nov 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 11 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP3
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
AK2 | NM_001625.4 | c.698_703delinsGACTCATAAACATAAACATAAACTCA | p.Lys233ArgfsTer59 | frameshift_variant | 6/6 | ENST00000672715.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
AK2 | ENST00000672715.1 | c.698_703delinsGACTCATAAACATAAACATAAACTCA | p.Lys233ArgfsTer59 | frameshift_variant | 6/6 | NM_001625.4 | P3 | ||
ENST00000427524.1 | n.246-17837_246-17832delinsTGAGTTTATGTTTATGTTTATGAGTC | intron_variant, non_coding_transcript_variant | 2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 15, 2024 | The c.698_703delinsGACTCATAAACATAAACATAAACTCA (p.K233Rfs*59) alteration, located in exon 6 (coding exon 6) of the AK2 gene, consists of a deletion of 6 and insertion of 26 nucleotides causing a translational frameshift at position 698 with a predicted alternate stop codon after 59 amino acids. This alteration occurs at the 3' terminus of the AK2 gene, is not expected to trigger nonsense-mediated mRNA decay and results in the elongation of the protein by 51 amino acids. This frameshift impacts the last 7 (2.9%) amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.