NM_001625.4:c.698_703delAAGACTinsGACTCATAAACATAAACATAAACTCA

Variant names:

• chr1-33013198-AGTCTT-TGAGTTTATGTTTATGTTTATGAGTC
• NM_001625.4:c.698_703delAAGACTinsGACTCATAAACATAAACATAAACTCA

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_001625.4(AK2):​c.698_703delAAGACTinsGACTCATAAACATAAACATAAACTCA​(p.Lys233ArgfsTer59) variant causes a frameshift, missense 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. KDL233RHINININS?) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AK2 NM_001625.4 frameshift, missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ENSG00000236065 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0306 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK2	NM_001625.4	c.698_703delAAGACTinsGACTCATAAACATAAACATAAACTCA	p.Lys233ArgfsTer59	frameshift_variant, missense_variant	Exon 6 of 6	ENST00000672715.1	NP_001616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AK2	ENST00000672715.1	c.698_703delAAGACTinsGACTCATAAACATAAACATAAACTCA	p.Lys233ArgfsTer59	frameshift_variant, missense_variant	Exon 6 of 6		NM_001625.4	ENSP00000499935.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-33478799;