rs137853206

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr1-33036828-T-C
• chr1-33036828-T-A
• chr1-33036828-T-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:5
• 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: ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK2	NM_001625.4	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	NP_001616.1	P54819-1
	AK2	NM_001319141.3		c.1A>G	p.Met1?	start_lost	Exon 1 of 8	NP_001306070.1	F8W1A4
	AK2	NM_013411.5		c.1A>G	p.Met1?	start_lost	Exon 1 of 7	NP_037543.1	P54819-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK2	ENST00000672715.1	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 6	ENSP00000499935.1	P54819-1
	AK2	ENST00000373449.7	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 7	ENSP00000362548.2	P54819-2
	AK2	ENST00000354858.11	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 5	ENSP00000346921.7	A0A5K1VW67

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

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Reticular dysgenesis (4)
1	-	-	Severe combined immunodeficiency disease (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.32	D
PhyloP100		3.8
PROVEAN	Benign	-0.98	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.035	D
Polyphen		0.91	P
Vest4		0.92
MutPred		1.0		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;