1-33013356-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_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

Scores

11
7
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 9.96
Variant links:
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 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
AK2NM_001625.4 linkuse as main transcriptc.545C>A p.Ala182Asp missense_variant 6/6 ENST00000672715.1 NP_001616.1 P54819-1A0A140VK93

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AK2ENST00000672715.1 linkuse as main transcriptc.545C>A p.Ala182Asp missense_variant 6/6 NM_001625.4 ENSP00000499935.1 P54819-1

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
LINK: link

Submissions by phenotype

Reticular dysgenesis Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsNov 27, 2019This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria providedclinical testingBiochemical Molecular Genetic Laboratory, King Abdulaziz Medical CityNov 12, 2020- -
Pathogenic, criteria provided, single submitterclinical testingCenter for Genomic Medicine, King Faisal Specialist Hospital and Research CenterMar 23, 2024- -
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingBlueprint GeneticsJan 16, 2019- -
Likely pathogenic, flagged submissionresearchCenter 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs559947967; hg19: chr1-33478957; API