rs267606646

Variant names:

• chr1-33013204-T-A
• rs267606646
• NM_001625.4:c.697A>T
• AK2 p.Lys233*

Your query was ambiguous. Multiple possible variants found:

• chr1-33013204-T-A
• chr1-33013204-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_001625.4(AK2):​c.697A>T​(p.Lys233*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AK2 NM_001625.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.24
• Publications: 1 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), Orphanet, ClinGen, G2P, Ambry Genetics

ENSG00000236065 (HGNC:58388):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0319 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-33013204-T-A is Pathogenic according to our data. Variant chr1-33013204-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18261.Status of the report is no_assertion_criteria_provided, 0 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.697A>T	p.Lys233*	stop_gained	Exon 6 of 6	NP_001616.1	P54819-1
	AK2	NM_001319140.2		c.553A>T	p.Lys185*	stop_gained	Exon 7 of 7	NP_001306069.1	P54819-6
	AK2	NM_001319143.2		c.*200A>T		3_prime_UTR	Exon 5 of 5	NP_001306072.1	G3V213

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK2	ENST00000672715.1	MANE Select	c.697A>T	p.Lys233*	stop_gained	Exon 6 of 6	ENSP00000499935.1	P54819-1
	AK2	ENST00000354858.11	TSL:1	c.571A>T	p.Lys191*	stop_gained	Exon 5 of 5	ENSP00000346921.7	A0A5K1VW67
	AK2	ENST00000373449.7	TSL:1	c.694+3A>T		splice_region intron	N/A	ENSP00000362548.2	P54819-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Reticular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		6.2
Mutation Taster		=17/183	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs267606646;

hg19: chr1-33478805;