dbSNP rs137853206: AK2:p.Met1? (chr1-33036828-T-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_StrongPS1_ModeratePM2

The NM_001625.4(AK2):c.1A>T(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.00000487 in 1,437,220 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

AK2
NM_001625.4 initiator_codon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.81

Publications

3 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: Likely_pathogenic. The variant received 8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 5 pathogenic variants. Next in-frame start position is after 49 codons. Genomic position: 33024516. Lost 0.201 part of the original CDS.

PS1

Another start lost variant in NM_001625.4 (AK2) was described as [Pathogenic] in ClinVar

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK2	NM_001625.4 link	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 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.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 6		NM_001625.4	ENSP00000499935.1		P54819-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000487

AC:

AN:

1437220

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

712930

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33026

American (AMR)

AF:

0.00

AC:

AN:

41622

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25634

East Asian (EAS)

AF:

0.00

AC:

AN:

38582

South Asian (SAS)

AF:

0.00

AC:

AN:

83006

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51282

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4154

European-Non Finnish (NFE)

AF:

0.00000636

AC:

AN:

1100618

Other (OTH)

AF:

0.00

AC:

AN:

59296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000268

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.013

.;.;T;T;.;T;.;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D;.;D;D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.93

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.0011

PhyloP100

3.8

PROVEAN

Benign

-0.62

.;N;N;N;N;N;N;.

REVEL

Uncertain

0.46

Sift

Benign

0.050

.;D;D;D;D;D;T;.

Sift4G

Benign

0.13

T;T;T;T;T;T;T;D

Polyphen

0.82, 0.80, 0.72

.;P;P;.;.;P;.;.

Vest4

0.91

MutPred

0.69

Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);Loss of solvent accessibility (P = 0.0217);

MVP

0.74

ClinPred

0.98

GERP RS

4.9

PromoterAI

-0.36

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.40

gMVP

0.76

Mutation Taster

=1/199

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over