NM_001625.4:c.453delC

Variant names:

• chr1-33014566-AG-A
• rs1553151177
• NM_001625.4:c.453delC

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_001625.4(AK2):​c.453delC​(p.Tyr152ThrfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S151S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AK2 NM_001625.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.234
• Publications: 1 publications found

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]

AK2 Gene-Disease associations (from GenCC):

• reticular dysgenesis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, Orphanet, G2P

ENSG00000236065 (HGNC:58388):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-33014566-AG-A is Pathogenic according to our data. Variant chr1-33014566-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18254.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001625.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK2	NM_001625.4	MANE Select	c.453delC	p.Tyr152ThrfsTer12	frameshift	Exon 5 of 6	NP_001616.1
	AK2	NM_001319141.3		c.453delC	p.Tyr152ThrfsTer12	frameshift	Exon 5 of 8	NP_001306070.1
	AK2	NM_013411.5		c.453delC	p.Tyr152ThrfsTer12	frameshift	Exon 5 of 7	NP_037543.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK2	ENST00000672715.1	MANE Select	c.453delC	p.Tyr152ThrfsTer12	frameshift	Exon 5 of 6	ENSP00000499935.1
	AK2	ENST00000373449.7	TSL:1	c.453delC	p.Tyr152ThrfsTer12	frameshift	Exon 5 of 7	ENSP00000362548.2
	AK2	ENST00000354858.11	TSL:1	c.327delC	p.Tyr110ThrfsTer12	frameshift	Exon 4 of 5	ENSP00000346921.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Reticular dysgenesis Pathogenic:1

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

AK2: PVS1:Strong, PM2, PP4:Moderate, PM3:Supporting, PP1

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs1553151177; hg19: chr1-33480167;