1-33036780-G-A

Variant names:

• chr1-33036780-G-A
• rs138577419
• NM_001625.4:c.49C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001319140.2(AK2):​c.-214C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,538 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: AK2 NM_001319140.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.25
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001319140.2. 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.49C>T	p.Arg17Trp	missense	Exon 1 of 6	NP_001616.1	P54819-1
	AK2	NM_001319140.2		c.-214C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001306069.1	P54819-6
	AK2	NM_001319139.3		c.-214C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 8	NP_001306068.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK2	ENST00000672715.1	MANE Select	c.49C>T	p.Arg17Trp	missense	Exon 1 of 6	ENSP00000499935.1	P54819-1
	AK2	ENST00000373449.7	TSL:1	c.49C>T	p.Arg17Trp	missense	Exon 1 of 7	ENSP00000362548.2	P54819-2
	AK2	ENST00000354858.11	TSL:1	c.49C>T	p.Arg17Trp	missense	Exon 1 of 5	ENSP00000346921.7	A0A5K1VW67

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000888 AC: 2 AN: 225300 AF XY: 0.00000818

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000997

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447538 Hom.: 0 Cov.: 31 AF XY: 0.00000417 AC XY: 3 AN XY: 718742

African (AFR) AF: 0.00 AC: 0 AN: 33240

American (AMR) AF: 0.00 AC: 0 AN: 43140

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25784

East Asian (EAS) AF: 0.00 AC: 0 AN: 39208

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 83950

European-Finnish (FIN) AF: 0.0000192 AC: 1 AN: 52086

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4686

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105744

Other (OTH) AF: 0.00 AC: 0 AN: 59700

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.3
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.024	D
Polyphen		0.28	B
Vest4		0.73
MutPred		0.65		Loss of disorder (P = 0.0011)
MVP		0.80
MPC		0.22
ClinPred		0.98	D
GERP RS		4.9
PromoterAI		-0.099	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.92
Mutation Taster		=34/66	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs138577419; hg19: chr1-33502381;