rs8192462

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000476.3(AK1):c.367G>C(p.Glu123Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0379 in 1,603,830 control chromosomes in the GnomAD database, including 1,477 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.027 ( 92 hom., cov: 32)

Exomes 𝑓: 0.039 ( 1385 hom. )

Consequence

AK1
NM_000476.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.74

Publications

20 publications found

Variant links:

Genes affected

AK1 (HGNC:361): (adenylate kinase 1) This gene encodes an adenylate kinase enzyme involved in energy metabolism and homeostasis of cellular adenine nucleotide ratios in different intracellular compartments. This gene is highly expressed in skeletal muscle, brain and erythrocytes. Certain mutations in this gene resulting in a functionally inadequate enzyme are associated with a rare genetic disorder causing nonspherocytic hemolytic anemia. Alternative splicing of this gene results in multiple transcript variants encoding different isoforms. This gene shares readthrough transcripts with the upstream ST6GALNAC6 gene. [provided by RefSeq, Jan 2022]

AK1 Gene-Disease associations (from GenCC):

hemolytic anemia due to adenylate kinase deficiency
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet

AK1 links:

ENSG00000257524 (HGNC:):

ENSG00000257524 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022380948).

BP6

Variant 9-127868470-C-G is Benign according to our data. Variant chr9-127868470-C-G is described in ClinVar as Benign. ClinVar VariationId is 402354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0895 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK1	NM_000476.3 link	c.367G>C	p.Glu123Gln	missense_variant	Exon 6 of 7	ENST00000644144.2	NP_000467.1	P00568Q6FGX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK1	ENST00000644144.2 link	c.367G>C	p.Glu123Gln	missense_variant	Exon 6 of 7	NM_000476.3	ENSP00000494600.1	P00568
ENSG00000257524	ENST00000646171.1 link	n.*400G>C		non_coding_transcript_exon_variant	Exon 12 of 13		ENSP00000495484.1	A0A2R8YFX0
ENSG00000257524	ENST00000646171.1 link	n.*400G>C		3_prime_UTR_variant	Exon 12 of 13		ENSP00000495484.1	A0A2R8YFX0

Frequencies

GnomAD3 genomes

AF:

0.0273

AC:

4153

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00649

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0196

Gnomad ASJ

AF:

0.0730

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0960

Gnomad FIN

AF:

0.0291

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0363

Gnomad OTH

AF:

0.0334

GnomAD2 exomes

AF:

0.0383

AC:

8841

AN:

231078

AF XY:

0.0416

show subpopulations

Gnomad AFR exome

AF:

0.00627

Gnomad AMR exome

AF:

0.0133

Gnomad ASJ exome

AF:

0.0751

Gnomad EAS exome

AF:

0.000173

Gnomad FIN exome

AF:

0.0319

Gnomad NFE exome

AF:

0.0372

Gnomad OTH exome

AF:

0.0418

GnomAD4 exome

AF:

0.0390

AC:

56553

AN:

1451578

Hom.:

1385

Cov.:

AF XY:

0.0408

AC XY:

29404

AN XY:

720990

show subpopulations

African (AFR)

AF:

0.00570

AC:

190

AN:

33330

American (AMR)

AF:

0.0146

AC:

632

AN:

43272

Ashkenazi Jewish (ASJ)

AF:

0.0695

AC:

1798

AN:

25876

East Asian (EAS)

AF:

0.000178

AC:

AN:

39414

South Asian (SAS)

AF:

0.0999

AC:

8422

AN:

84276

European-Finnish (FIN)

AF:

0.0329

AC:

1732

AN:

52694

Middle Eastern (MID)

AF:

0.0385

AC:

216

AN:

5614

European-Non Finnish (NFE)

AF:

0.0372

AC:

41148

AN:

1107128

Other (OTH)

AF:

0.0402

AC:

2408

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

3486

6972

10458

13944

17430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1596

3192

4788

6384

7980

<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:

0.0273

AC:

4158

AN:

152252

Hom.:

Cov.:

AF XY:

0.0277

AC XY:

2065

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.00650

AC:

270

AN:

41542

American (AMR)

AF:

0.0195

AC:

299

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0730

AC:

253

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0967

AC:

467

AN:

4828

European-Finnish (FIN)

AF:

0.0291

AC:

309

AN:

10618

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0363

AC:

2467

AN:

67986

Other (OTH)

AF:

0.0331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

208

415

623

830

1038

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

124

186

248

310

<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:

0.0372

Hom.:

106

Bravo

AF:

0.0246

ESP6500AA

AF:

0.00545

AC:

ESP6500EA

AF:

0.0367

AC:

316

ExAC

AF:

0.0369

AC:

4482

Asia WGS

AF:

0.0400

AC:

137

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 09, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Hemolytic anemia due to adenylate kinase deficiency

Benign:1

Nov 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

D;D;D;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.96

.;.;D;D

MetaRNN

Benign

0.0022

T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Uncertain

2.1

M;M;M;.

PhyloP100

5.7

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

N;.;N;N

REVEL

Benign

0.21

Sift

Benign

0.081

T;.;T;T

Sift4G

Uncertain

0.059

T;.;T;T

Polyphen

0.15

B;B;B;.

Vest4

0.26

MPC

0.35

ClinPred

0.012

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.67

gMVP

0.69

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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