NM_001625.4:c.*193_*196dupTGTG

Variant names:

• chr1-33012984-G-GCACA
• rs368005323
• NM_001625.4:c.*193_*196dupTGTG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS1

The NM_001625.4(AK2):​c.*193_*196dupTGTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000293 in 1,501,196 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: 𝑓 0.000093 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: AK2 NM_001625.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.229
• 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: ClinGen, Orphanet, Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000236065 (HGNC:58388):

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000093 (14/150538) while in subpopulation AFR AF = 0.000316 (13/41114). AF 95% confidence interval is 0.000187. There are 0 homozygotes in GnomAd4. There are 9 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.*193_*196dupTGTG		3_prime_UTR	Exon 6 of 6	NP_001616.1	P54819-1
	AK2	NM_001319140.2		c.*193_*196dupTGTG		3_prime_UTR	Exon 7 of 7	NP_001306069.1	P54819-6
	AK2	NM_001319143.2		c.*416_*419dupTGTG		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.*193_*196dupTGTG		3_prime_UTR	Exon 6 of 6	ENSP00000499935.1	P54819-1
	AK2	ENST00000354858.11	TSL:1	c.*193_*196dupTGTG		3_prime_UTR	Exon 5 of 5	ENSP00000346921.7	A0A5K1VW67
	AK2	ENST00000373449.7	TSL:1	c.694+219_694+222dupTGTG		intron	N/A	ENSP00000362548.2	P54819-2

Frequencies

GnomAD3 genomes AF: 0.0000931 AC: 14 AN: 150438 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000317

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.0000806 AC: 5 AN: 62018 AF XY: 0.0000909

Gnomad AFR exome AF: 0.00101

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000222 AC: 30 AN: 1350658 Hom.: 0 Cov.: 29 AF XY: 0.0000283 AC XY: 19 AN XY: 671336

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

African (AFR) AF: 0.000330 AC: 10 AN: 30336

American (AMR) AF: 0.00 AC: 0 AN: 40584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24038

East Asian (EAS) AF: 0.00 AC: 0 AN: 35936

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 79884

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5286

European-Non Finnish (NFE) AF: 0.0000172 AC: 18 AN: 1044310

Other (OTH) AF: 0.00 AC: 0 AN: 55718

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000632316), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000930 AC: 14 AN: 150538 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9 AN XY: 73528

African (AFR) AF: 0.000316 AC: 13 AN: 41114

American (AMR) AF: 0.00 AC: 0 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10260

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67424

Other (OTH) AF: 0.000481 AC: 1 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000110

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs368005323; hg19: chr1-33478585;