1-33021406-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001625.4(AK2):c.386G>A(p.Ser129Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,614,038 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S129R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0037 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0058 ( 35 hom. )

Consequence

AK2
NM_001625.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 2.40

Publications

8 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013360918).

BP6

Variant 1-33021406-C-T is Benign according to our data. Variant chr1-33021406-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 517906.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00372 (566/152268) while in subpopulation NFE AF = 0.00645 (439/68018). AF 95% confidence interval is 0.00596. There are 2 homozygotes in GnomAd4. There are 265 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK2	NM_001625.4 link	c.386G>A	p.Ser129Asn	missense_variant	Exon 4 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.386G>A	p.Ser129Asn	missense_variant	Exon 4 of 6		NM_001625.4	ENSP00000499935.1		P54819-1

Frequencies

GnomAD3 genomes

AF:

0.00373

AC:

567

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00807

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00645

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.00411

AC:

1032

AN:

251272

AF XY:

0.00457

show subpopulations

Gnomad AFR exome

AF:

0.00111

Gnomad AMR exome

AF:

0.000896

Gnomad ASJ exome

AF:

0.00715

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000416

Gnomad NFE exome

AF:

0.00597

Gnomad OTH exome

AF:

0.00342

GnomAD4 exome

AF:

0.00579

AC:

8470

AN:

1461770

Hom.:

Cov.:

AF XY:

0.00575

AC XY:

4182

AN XY:

727192

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

33478

American (AMR)

AF:

0.000760

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00624

AC:

163

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00560

AC:

483

AN:

86248

European-Finnish (FIN)

AF:

0.000431

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00537

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00664

AC:

7387

AN:

1111924

Other (OTH)

AF:

0.00518

AC:

313

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

424

848

1271

1695

2119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

292

584

876

1168

1460

<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:

0.00372

AC:

566

AN:

152268

Hom.:

Cov.:

AF XY:

0.00356

AC XY:

265

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

41562

American (AMR)

AF:

0.00111

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00807

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00353

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00645

AC:

439

AN:

68018

Other (OTH)

AF:

0.000475

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00510

Hom.:

Bravo

AF:

0.00346

TwinsUK

AF:

0.00728

AC:

ALSPAC

AF:

0.00545

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00422

AC:

513

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00660

EpiControl

AF:

0.00664

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Reticular dysgenesis

Uncertain:1Benign:1

May 09, 2018

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Dec 21, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

AK2-related disorder

Benign:1

May 06, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

not provided

Benign:1

Feb 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

AK2: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.16

.;T;T;T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.014

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Benign

0.017

MetaRNN

Benign

0.013

T;T;T;T;T

MetaSVM

Benign

-0.70

MutationAssessor

Benign

-0.69

N;.;.;N;.

PhyloP100

2.4

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.20

N;N;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.46

T;T;T;T;T

Sift4G

Benign

0.51

T;T;T;T;T

Polyphen

0.0

B;B;.;B;.

Vest4

0.49

MVP

0.65

MPC

0.18

ClinPred

0.018

GERP RS

4.4

Varity_R

0.11

gMVP

0.46

Mutation Taster

=95/5

polymorphism

(source)

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

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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