1-33036828-T-C

Variant names:

• chr1-33036828-T-C
• rs137853206
• NM_001625.4:c.1A>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_001625.4(AK2):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000765 in 1,437,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000077 (0 hom.)
• Consequence: AK2 NM_001625.4 start_lost
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 3.81
• Publications: 3 publications found

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

ENSG00000236065 (HGNC:58388):

ACMG classification

Our verdict: Pathogenic. The variant received 14 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.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-33036828-T-C is Pathogenic according to our data. Variant chr1-33036828-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 18252.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	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENST00000672715.1	NP_001616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AK2	ENST00000672715.1	c.1A>G	p.Met1?	start_lost	Exon 1 of 6		NM_001625.4	ENSP00000499935.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000957 AC: 2 AN: 208954 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000765 AC: 11 AN: 1437220 Hom.: 0 Cov.: 31 AF XY: 0.00000561 AC XY: 4 AN XY: 712930

African (AFR) AF: 0.00 AC: 0 AN: 33026

American (AMR) AF: 0.0000240 AC: 1 AN: 41622

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25634

East Asian (EAS) AF: 0.00 AC: 0 AN: 38582

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 83006

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4154

European-Non Finnish (NFE) AF: 0.00000727 AC: 8 AN: 1100618

Other (OTH) AF: 0.00 AC: 0 AN: 59296

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Reticular dysgenesis Pathogenic:3

Dec 02, 2023

Laboratory of Hereditary Immune Disorders, Research Centre for Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The start-loss variant NM_001625.4(AK2):c.1A>G, p.(Met1?) was identified in a homozygous state in a proband diagnosed with reticular dysgenesis in Russian pilot NBS project covering more than 200,000 newborns. This variant has been previously reported in the literature multiple times (PMIDs: 19043417) and is listed in gnomAD v2.1.1 two times in heterozygous individuals. The loss of translation initiation codon should lead to near complete reduction in translation level or synthesis of N-terminally truncated protein (the next ATG-codon located in position Met49. Taken together, the variant meets the following ACMG/AMP criteria and can be classified as pathogenic with PM2, PP3, PVS1, PP5, PP4 criteria. -

Jan 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 01, 2024

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The start lost c.1A>G (p.Met1?) variant in AK2 gene has been reported previously in compound heterozygous state in an individual affected with reticular dysgenesis (Pannicke et al., 2009).The p.Met1? variant is predicted to disrupt the initiation codon, and thus potentially may interfere with protein expression -

Severe combined immunodeficiency disease Pathogenic:1

Apr 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: AK2 c.1A>G (p.Met1Val) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. An alternative downstream in-frame start codon (Met49) is located in the encoded protein. An activation of potential downstream translation initiation site would result in a shortened protein missing the first 48 amino acids from the protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-06 in 208954 control chromosomes. c.1A>G has been observed as a biallelic genotype in multiple individuals affected with Reticular Dysgenesis (e.g. Pannicke_2009, Guilcher_2017, Marakhonov_2024). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27913909, 28331055, 38578360, 19043417). ClinVar contains an entry for this variant (Variation ID: 18252). Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.29
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	.;.;T;T;.;T;.;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D;.;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.32	D
PhyloP100		3.8
PROVEAN	Benign	-0.98	.;N;N;N;N;N;N;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	.;D;D;D;D;D;D;.
Sift4G	Uncertain	0.035	D;D;D;D;D;D;D;D
Polyphen		0.91, 0.95, 0.86	.;P;P;.;.;P;.;.
Vest4		0.92
MutPred		1.0		Loss of glycosylation at P6 (P = 0.2007);Loss of glycosylation at P6 (P = 0.2007);Loss of glycosylation at P6 (P = 0.2007);Loss of glycosylation at P6 (P = 0.2007);Loss of glycosylation at P6 (P = 0.2007);Loss of glycosylation at P6 (P = 0.2007);Loss of glycosylation at P6 (P = 0.2007);Loss of glycosylation at P6 (P = 0.2007);
MVP		0.81
ClinPred		0.94	D
GERP RS		4.9
PromoterAI		-0.19	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.66
gMVP		0.84
Mutation Taster		=1/199	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137853206; hg19: chr1-33502429; COSMIC: COSV61467031; COSMIC: COSV61467031;