rs12116440

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001625.4(AK2):​c.625G>T​(p.Ala209Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. A209T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

AK2
NM_001625.4 missense

Scores

1
2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.03
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.28383854).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AK2NM_001625.4 linkuse as main transcriptc.625G>T p.Ala209Ser missense_variant 6/6 ENST00000672715.1 NP_001616.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AK2ENST00000672715.1 linkuse as main transcriptc.625G>T p.Ala209Ser missense_variant 6/6 NM_001625.4 ENSP00000499935 P3P54819-1
ENST00000427524.1 linkuse as main transcriptn.246-17759C>A intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251440
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135886
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461862
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Reticular dysgenesis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 03, 2018This variant is not present in population databases (ExAC no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with AK2-related disease. This sequence change replaces alanine with serine at codon 209 of the AK2 protein (p.Ala209Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.096
BayesDel_addAF
Benign
-0.00065
T
BayesDel_noAF
Benign
-0.16
CADD
Benign
17
DANN
Benign
0.97
DEOGEN2
Benign
0.0039
.;T;T;T
Eigen
Benign
-0.19
Eigen_PC
Benign
-0.049
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D;D;D
M_CAP
Benign
0.027
D
MetaRNN
Benign
0.28
T;T;T;T
MetaSVM
Benign
-0.60
T
MutationAssessor
Uncertain
2.4
M;.;.;M
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-0.22
N;N;N;N
REVEL
Benign
0.29
Sift
Benign
0.41
T;T;T;T
Sift4G
Benign
0.68
T;T;T;T
Polyphen
0.015
B;D;.;B
Vest4
0.47
MutPred
0.24
Gain of disorder (P = 0.0209);.;Gain of disorder (P = 0.0209);Gain of disorder (P = 0.0209);
MVP
0.58
MPC
0.26
ClinPred
0.41
T
GERP RS
4.3
Varity_R
0.14
gMVP
0.47

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: rs12116440; hg19: chr1-33478877; API