1-33010834-C-A

Variant names:

• chr1-33010834-C-A
• rs1045885332
• NM_001625.4:c.*2347G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_013411.5(AK2):​c.695-1G>T variant causes a splice acceptor, intron change. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AK2 NM_013411.5 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9959
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.78
• Publications: 5 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: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease,

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013411.5. 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.*2347G>T		3_prime_UTR	Exon 6 of 6	NP_001616.1	P54819-1
	AK2	NM_001319140.2		c.*2347G>T		3_prime_UTR	Exon 7 of 7	NP_001306069.1	P54819-6
	AK2	NM_001319143.2		c.*2570G>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.*2347G>T		3_prime_UTR	Exon 6 of 6	ENSP00000499935.1	P54819-1
	AK2	ENST00000354858.11	TSL:1	c.*2347G>T		3_prime_UTR	Exon 5 of 5	ENSP00000346921.7	A0A5K1VW67
	AK2	ENST00000373449.7	TSL:1	c.695-1G>T		splice_acceptor intron	N/A	ENSP00000362548.2	P54819-2

Frequencies

GnomAD3 genomes AF: 0.000354 AC: 24 AN: 67706 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000751

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000606

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000459

Gnomad FIN AF: 0.000662

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000659

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1385206 Hom.: 0 Cov.: 44 AF XY: 0.00 AC XY: 0 AN XY: 691756

African (AFR) AF: 0.00 AC: 0 AN: 32056

American (AMR) AF: 0.00 AC: 0 AN: 44000

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25482

East Asian (EAS) AF: 0.00 AC: 0 AN: 39032

South Asian (SAS) AF: 0.00 AC: 0 AN: 83920

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1047334

Other (OTH) AF: 0.00 AC: 0 AN: 57774

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000354 AC: 24 AN: 67824 Hom.: 0 Cov.: 24 AF XY: 0.000495 AC XY: 16 AN XY: 32322

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000747 AC: 14 AN: 18744

American (AMR) AF: 0.000604 AC: 4 AN: 6618

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1466

East Asian (EAS) AF: 0.00 AC: 0 AN: 2422

South Asian (SAS) AF: 0.000459 AC: 1 AN: 2178

European-Finnish (FIN) AF: 0.000662 AC: 3 AN: 4532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 150

European-Non Finnish (NFE) AF: 0.0000659 AC: 2 AN: 30352

Other (OTH) AF: 0.00 AC: 0 AN: 968

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00109 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86

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: rs1045885332; hg19: chr1-33476435; COSMIC: COSV61467867; COSMIC: COSV61467867;