1-33036804-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001625.4(AK2):c.25G>A(p.Glu9Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000241 in 1,596,510 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00025 ( 5 hom. )

Consequence

AK2
NM_001625.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:4

Conservation

PhyloP100: 0.573

Publications

3 publications found

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]

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

AK2 links:

ENSG00000236065 (HGNC:58388):

ENSG00000236065 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005564481).

BP6

Variant 1-33036804-C-T is Benign according to our data. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-33036804-C-T is described in CliVar as Likely_benign. Clinvar id is 737934.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000158 (24/152348) while in subpopulation SAS AF = 0.00435 (21/4830). AF 95% confidence interval is 0.00291. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK2	NM_001625.4 link	c.25G>A	p.Glu9Lys	missense_variant	Exon 1 of 6	ENST00000672715.1	NP_001616.1	P54819-1A0A140VK93

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AK2	ENST00000672715.1 link	c.25G>A	p.Glu9Lys	missense_variant	Exon 1 of 6		NM_001625.4	ENSP00000499935.1		P54819-1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000560

AC:

123

AN:

219838

AF XY:

0.000806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.000250

AC:

361

AN:

1444162

Hom.:

Cov.:

AF XY:

0.000388

AC XY:

278

AN XY:

716930

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33176

American (AMR)

AF:

0.00

AC:

AN:

42688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25750

East Asian (EAS)

AF:

0.00

AC:

AN:

39002

South Asian (SAS)

AF:

0.00409

AC:

342

AN:

83678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51648

Middle Eastern (MID)

AF:

0.000233

AC:

AN:

4284

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1104378

Other (OTH)

AF:

0.000269

AC:

AN:

59558

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

126

158

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000158

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41580

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00435

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000883

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000596

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Reticular dysgenesis

Benign:1

Dec 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

AK2-related disorder

Benign:1

Apr 13, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.018

.;.;T;T;.;T;.;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.93

D;D;D;D;.;D;D;D

M_CAP

Benign

0.059

MetaRNN

Benign

0.0056

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

0.050

.;N;.;.;.;N;.;.

PhyloP100

0.57

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.40

.;N;N;N;N;N;N;.

REVEL

Benign

0.13

Sift

Benign

0.50

.;T;T;T;T;T;T;.

Sift4G

Benign

0.33

T;T;T;T;T;T;T;T

Polyphen

0.68, 0.76, 0.70

.;P;P;.;.;P;.;.

Vest4

0.32

MutPred

0.23

Gain of methylation at E9 (P = 0.0129);Gain of methylation at E9 (P = 0.0129);Gain of methylation at E9 (P = 0.0129);Gain of methylation at E9 (P = 0.0129);Gain of methylation at E9 (P = 0.0129);Gain of methylation at E9 (P = 0.0129);Gain of methylation at E9 (P = 0.0129);Gain of methylation at E9 (P = 0.0129);

MVP

0.56

MPC

0.24

ClinPred

0.020

GERP RS

0.87

PromoterAI

-0.045

Neutral

(source)

Varity_R

0.13

gMVP

0.70

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over