chr1-33012984-GCA-G

Variant names:

• chr1-33012984-GCA-G
• rs368005323
• NM_001625.4:c.*195_*196delTG

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP6_Moderate BS1

The NM_001625.4(AK2):​c.*195_*196delTG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,168,730 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00031 (0 hom., cov: 32)
  • Exomes 𝑓: 0.014 (0 hom.)
• Consequence: AK2 NM_001625.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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.

• PM2: Variant has high frequency in the EAS (0.0426) population. However there is too low homozygotes in high coverage region: (expected more than 41, got 0).
• BP6: Variant 1-33012984-GCA-G is Benign according to our data. Variant chr1-33012984-GCA-G is described in ClinVar as Benign. ClinVar VariationId is 1232355.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000313 (47/150270) while in subpopulation SAS AF = 0.00084 (4/4764). AF 95% confidence interval is 0.000484. There are 0 homozygotes in GnomAd4. There are 30 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.*195_*196delTG		3_prime_UTR	Exon 6 of 6	NP_001616.1	P54819-1
	AK2	NM_001319140.2		c.*195_*196delTG		3_prime_UTR	Exon 7 of 7	NP_001306069.1	P54819-6
	AK2	NM_001319143.2		c.*418_*419delTG		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.*195_*196delTG		3_prime_UTR	Exon 6 of 6	ENSP00000499935.1	P54819-1
	AK2	ENST00000354858.11	TSL:1	c.*195_*196delTG		3_prime_UTR	Exon 5 of 5	ENSP00000346921.7	A0A5K1VW67
	AK2	ENST00000373449.7	TSL:1	c.694+221_694+222delTG		intron	N/A	ENSP00000362548.2	P54819-2

Frequencies

GnomAD3 genomes AF: 0.000313 AC: 47 AN: 150170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000683

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000839

Gnomad FIN AF: 0.000491

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000149

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0974 AC: 6042 AN: 62018 AF XY: 0.103

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0703

Gnomad ASJ exome AF: 0.0453

Gnomad EAS exome AF: 0.108

Gnomad FIN exome AF: 0.0945

Gnomad NFE exome AF: 0.109

Gnomad OTH exome AF: 0.0741

GnomAD4 exome AF: 0.0137 AC: 13915 AN: 1018460 Hom.: 0 AF XY: 0.0149 AC XY: 7376 AN XY: 495884

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

African (AFR) AF: 0.0196 AC: 407 AN: 20716

American (AMR) AF: 0.0390 AC: 920 AN: 23604

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 411 AN: 15572

East Asian (EAS) AF: 0.0448 AC: 1091 AN: 24352

South Asian (SAS) AF: 0.0175 AC: 734 AN: 41966

European-Finnish (FIN) AF: 0.0440 AC: 1069 AN: 24312

Middle Eastern (MID) AF: 0.0230 AC: 93 AN: 4044

European-Non Finnish (NFE) AF: 0.0102 AC: 8360 AN: 822670

Other (OTH) AF: 0.0201 AC: 830 AN: 41224

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000313 AC: 47 AN: 150270 Hom.: 0 Cov.: 32 AF XY: 0.000409 AC XY: 30 AN XY: 73384

African (AFR) AF: 0.000682 AC: 28 AN: 41080

American (AMR) AF: 0.00 AC: 0 AN: 15096

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3434

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.000840 AC: 4 AN: 4764

European-Finnish (FIN) AF: 0.000491 AC: 5 AN: 10184

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

European-Non Finnish (NFE) AF: 0.000149 AC: 10 AN: 67302

Other (OTH) AF: 0.00 AC: 0 AN: 2078

Alfa AF: 0.104 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.23
Mutation Taster		=100/0	polymorphism

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; COSMIC: COSV61467872; COSMIC: COSV61467872;