Genetic Variant AK5:p.Lys203Lys (chr1-77297857-A-G) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PP3_ModerateBP7BS1BS2

The NM_174858.3(AK5):c.609A>G(p.Lys203Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00261 in 1,612,672 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.014 ( 55 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 44 hom. )

Consequence

AK5
NM_174858.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.94

Publications

10 publications found

Variant links:

Genes affected

AK5 (HGNC:365): (adenylate kinase 5) This gene encodes a member of the adenylate kinase family, which is involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of phosphate groups among adenine nucleotides. This member is related to the UMP/CMP kinase of several species. It is located in the cytosol and expressed exclusively in brain. Alternatively spliced transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

AK5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PP3

BayesDel_noAF computational evidence supports a deleterious effect, 0.35

BP7

Synonymous conserved (PhyloP=1.94 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0145 (2204/152326) while in subpopulation AFR AF = 0.0503 (2090/41584). AF 95% confidence interval is 0.0485. There are 55 homozygotes in GnomAd4. There are 1040 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 55 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK5	NM_174858.3 link	c.609A>G	p.Lys203Lys	synonymous_variant	Exon 5 of 14	ENST00000354567.7	NP_777283.1	Q9Y6K8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AK5	ENST00000354567.7 link	c.609A>G	p.Lys203Lys	synonymous_variant	Exon 5 of 14	1	NM_174858.3	ENSP00000346577.2		Q9Y6K8-1

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2196

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0502

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00511

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.0115

GnomAD4 exome

AF:

0.00137

AC:

2000

AN:

1460346

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

856

AN XY:

726310

show subpopulations

African (AFR)

AF:

0.0488

AC:

1630

AN:

33412

American (AMR)

AF:

0.00250

AC:

111

AN:

44480

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.0000701

AC:

AN:

85590

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.000696

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000666

AC:

AN:

1111636

Other (OTH)

AF:

0.00290

AC:

175

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

105

210

315

420

525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

168

224

280

<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:

0.0145

AC:

2204

AN:

152326

Hom.:

Cov.:

AF XY:

0.0140

AC XY:

1040

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.0503

AC:

2090

AN:

41584

American (AMR)

AF:

0.00503

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68024

Other (OTH)

AF:

0.0114

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

194

292

389

486

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00645

Hom.:

Bravo

AF:

0.0156

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Pathogenic

0.35

CADD

Benign

7.9

(source)

PhyloP100

1.9

Mutation Taster

=99/1

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over