1-33013330-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP3BP4_StrongBP6_Very_Strong

The NM_001625.4(AK2):c.571C>G(p.His191Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 145,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AK2
NM_001625.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 9.96

Publications

18 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 -11 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, phyloP100way_vertebrate, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.004391223).

BP6

Variant 1-33013330-G-C is Benign according to our data. Variant chr1-33013330-G-C is described in ClinVar as Benign. ClinVar VariationId is 529737.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK2	NM_001625.4 link	c.571C>G	p.His191Asp	missense_variant	Exon 6 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.571C>G	p.His191Asp	missense_variant	Exon 6 of 6		NM_001625.4	ENSP00000499935.1		P54819-1

Frequencies

GnomAD3 genomes

AF:

0.00310

AC:

450

AN:

145098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000962

Gnomad AMI

AF:

0.00112

Gnomad AMR

AF:

0.00179

Gnomad ASJ

AF:

0.00419

Gnomad EAS

AF:

0.00262

Gnomad SAS

AF:

0.00155

Gnomad FIN

AF:

0.000405

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.00511

Gnomad OTH

AF:

0.00656

GnomAD2 exomes

AF:

0.0346

AC:

5457

AN:

157516

AF XY:

0.0353

show subpopulations

Gnomad AFR exome

AF:

0.0514

Gnomad AMR exome

AF:

0.0241

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.0262

Gnomad FIN exome

AF:

0.0310

Gnomad NFE exome

AF:

0.0454

Gnomad OTH exome

AF:

0.0337

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00840

AC:

10081

AN:

1200458

Hom.:

Cov.:

AF XY:

0.00919

AC XY:

5500

AN XY:

598208

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0102

AC:

290

AN:

28352

American (AMR)

AF:

0.0294

AC:

1127

AN:

38340

Ashkenazi Jewish (ASJ)

AF:

0.00573

AC:

137

AN:

23908

East Asian (EAS)

AF:

0.0155

AC:

558

AN:

35964

South Asian (SAS)

AF:

0.00942

AC:

719

AN:

76322

European-Finnish (FIN)

AF:

0.0174

AC:

713

AN:

41030

Middle Eastern (MID)

AF:

0.00313

AC:

AN:

5114

European-Non Finnish (NFE)

AF:

0.00677

AC:

6086

AN:

899626

Other (OTH)

AF:

0.00840

AC:

435

AN:

51802

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.239

Heterozygous variant carriers

1714

3429

5143

6858

8572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

186

372

558

744

930

<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:

0.00311

AC:

452

AN:

145184

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

292

AN XY:

70516

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000984

AC:

AN:

39616

American (AMR)

AF:

0.00186

AC:

AN:

14508

Ashkenazi Jewish (ASJ)

AF:

0.00419

AC:

AN:

3344

East Asian (EAS)

AF:

0.00283

AC:

AN:

4942

South Asian (SAS)

AF:

0.00133

AC:

AN:

4516

European-Finnish (FIN)

AF:

0.000405

AC:

AN:

9882

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.00511

AC:

333

AN:

65202

Other (OTH)

AF:

0.00651

AC:

AN:

1998

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.258

Heterozygous variant carriers

105

158

210

263

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:

0.156

Hom.:

ExAC

AF:

0.320

AC:

38814

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Reticular dysgenesis

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

.;D;D;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.71

T;T;T;T

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

L;.;.;L

PhyloP100

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-8.6

D;D;D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.63

P;D;.;P

Vest4

0.32

MPC

0.88

ClinPred

0.056

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.79

Mutation Taster

=5/95

disease causing

(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