Genetic Variant AK2:c.*3356G>A (chr1-33009825-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001625.4(AK2):c.*3356G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 454,208 control chromosomes in the GnomAD database, including 17,541 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.22 ( 4490 hom., cov: 32)

Exomes 𝑓: 0.28 ( 13051 hom. )

Consequence

AK2
NM_001625.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.36

Publications

13 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: ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

AK2 links:

ENSG00000236065 (HGNC:58388):

ENSG00000236065 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.348 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001625.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AK2	NM_001625.4	MANE Select	c.*3356G>A	3_prime_UTR	Exon 6 of 6	NP_001616.1	P54819-1
AK2	NM_001319141.3		c.*1053G>A	3_prime_UTR	Exon 8 of 8	NP_001306070.1	F8W1A4
AK2	NM_013411.5		c.*1004G>A	3_prime_UTR	Exon 7 of 7	NP_037543.1	P54819-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
AK2	ENST00000672715.1	MANE Select	c.*3356G>A	3_prime_UTR	Exon 6 of 6	ENSP00000499935.1	P54819-1
AK2	ENST00000373449.7	TSL:1	c.*1004G>A	3_prime_UTR	Exon 7 of 7	ENSP00000362548.2	P54819-2
AK2	ENST00000354858.11	TSL:1	c.*3356G>A	3_prime_UTR	Exon 5 of 5	ENSP00000346921.7	A0A5K1VW67

Frequencies

GnomAD3 genomes

AF:

0.218

AC:

33185

AN:

151912

Hom.:

4491

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0587

Gnomad AMI

AF:

0.117

Gnomad AMR

AF:

0.356

Gnomad ASJ

AF:

0.194

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.305

Gnomad FIN

AF:

0.277

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.268

Gnomad OTH

AF:

0.223

GnomAD2 exomes

AF:

0.292

AC:

39883

AN:

136480

AF XY:

0.289

show subpopulations

Gnomad AFR exome

AF:

0.0552

Gnomad AMR exome

AF:

0.445

Gnomad ASJ exome

AF:

0.199

Gnomad EAS exome

AF:

0.280

Gnomad FIN exome

AF:

0.272

Gnomad NFE exome

AF:

0.263

Gnomad OTH exome

AF:

0.260

GnomAD4 exome

AF:

0.283

AC:

85455

AN:

302178

Hom.:

13051

Cov.:

AF XY:

0.283

AC XY:

48826

AN XY:

172232

show subpopulations

African (AFR)

AF:

0.0578

AC:

494

AN:

8548

American (AMR)

AF:

0.445

AC:

12129

AN:

27272

Ashkenazi Jewish (ASJ)

AF:

0.197

AC:

2128

AN:

10786

East Asian (EAS)

AF:

0.267

AC:

2462

AN:

9210

South Asian (SAS)

AF:

0.315

AC:

18813

AN:

59646

European-Finnish (FIN)

AF:

0.271

AC:

3458

AN:

12770

Middle Eastern (MID)

AF:

0.211

AC:

243

AN:

1150

European-Non Finnish (NFE)

AF:

0.266

AC:

42306

AN:

158750

Other (OTH)

AF:

0.244

AC:

3422

AN:

14046

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

5147

10293

15440

20586

25733

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

312

624

936

1248

1560

<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:

0.218

AC:

33182

AN:

152030

Hom.:

4490

Cov.:

AF XY:

0.225

AC XY:

16698

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.0585

AC:

2430

AN:

41504

American (AMR)

AF:

0.356

AC:

5431

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.194

AC:

671

AN:

3466

East Asian (EAS)

AF:

0.270

AC:

1392

AN:

5164

South Asian (SAS)

AF:

0.305

AC:

1470

AN:

4816

European-Finnish (FIN)

AF:

0.277

AC:

2921

AN:

10540

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.268

AC:

18227

AN:

67962

Other (OTH)

AF:

0.221

AC:

464

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1259

2519

3778

5038

6297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

364

728

1092

1456

1820

<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:

0.245

Hom.:

6387

Bravo

AF:

0.216

Asia WGS

AF:

0.211

AC:

732

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.15

(source)

DANN

Benign

0.57

PhyloP100

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over