1-33013356-G-T

Position:

• chr1-33013356-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_001625.4(AK2):​c.545C>A​(p.Ala182Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A182V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AK2 NM_001625.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.96

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001625.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.861
• PP5: Variant 1-33013356-G-T is Pathogenic according to our data. Variant chr1-33013356-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 190980.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-33013356-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AK2	NM_001625.4	c.545C>A	p.Ala182Asp	missense_variant	6/6	ENST00000672715.1	NP_001616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AK2	ENST00000672715.1	c.545C>A	p.Ala182Asp	missense_variant	6/6		NM_001625.4	ENSP00000499935.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Reticular dysgenesis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Nov 27, 2019	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Nov 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 23, 2024	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Jan 16, 2019	- -
Likely pathogenic, flagged submission	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	.;D;D;D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.86	D;D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.2	M;.;.;M
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		0.84	P;D;.;P
Vest4		0.91
MutPred		0.65		Gain of ubiquitination at K184 (P = 0.0402);.;Gain of ubiquitination at K184 (P = 0.0402);Gain of ubiquitination at K184 (P = 0.0402);
MVP		0.97
MPC		0.82
ClinPred		0.98	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.93
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs559947967; hg19: chr1-33478957;