rs267606643

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS1_ModeratePM2PP3_ModeratePP5_Moderate

The NM_001625.4(AK2):ā€‹c.494A>Gā€‹(p.Asp165Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā˜…). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

AK2
NM_001625.4 missense

Scores

14
4
1

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.99
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 Likely_pathogenic. Variant got 8 ACMG points.

PS1
Transcript NM_001625.4 (AK2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 1-33014526-T-C is Pathogenic according to our data. Variant chr1-33014526-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 18256.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
AK2NM_001625.4 linkuse as main transcriptc.494A>G p.Asp165Gly missense_variant 5/6 ENST00000672715.1 NP_001616.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
AK2ENST00000672715.1 linkuse as main transcriptc.494A>G p.Asp165Gly missense_variant 5/6 NM_001625.4 ENSP00000499935 P3P54819-1
ENST00000427524.1 linkuse as main transcriptn.246-16509T>C intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460124
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
726366
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.0000498
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Reticular dysgenesis Pathogenic:2
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 03, 2022This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 165 of the AK2 protein (p.Asp165Gly). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 disruptive. ClinVar contains an entry for this variant (Variation ID: 18256). This variant is also known as c.546A>G. This missense change has been observed in individual(s) with severe combined immunodeficiency (PMID: 19043416). -
Pathogenic, no assertion criteria providedliterature onlyOMIMJan 01, 2009- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.44
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
36
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.59
.;D;D;D
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.91
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Pathogenic
0.31
D
MetaRNN
Pathogenic
0.96
D;D;D;D
MetaSVM
Pathogenic
0.84
D
MutationAssessor
Pathogenic
5.3
H;.;.;H
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Uncertain
0.60
T
PROVEAN
Pathogenic
-6.9
D;D;D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D;D;D
Sift4G
Uncertain
0.0060
D;D;D;D
Polyphen
1.0
D;D;.;D
Vest4
0.97
MutPred
0.82
Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP
0.96
MPC
0.86
ClinPred
1.0
D
GERP RS
5.1
Varity_R
0.99
gMVP
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.98
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.98
Position offset: 1
DS_DL_spliceai
0.22
Position offset: -4

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: rs267606643; hg19: chr1-33480127; API