1-33013276-C-T

Variant names:

• chr1-33013276-C-T
• rs12116440
• NM_001625.4:c.625G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001625.4(AK2):​c.625G>A​(p.Ala209Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0121 in 1,614,092 control chromosomes in the GnomAD database, including 134 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A209S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0077 (8 hom., cov: 32)
  • Exomes 𝑓: 0.013 (126 hom.)
• Consequence: AK2 NM_001625.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 5.03
• Publications: 16 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007793486).
• BP6: Variant 1-33013276-C-T is Benign according to our data. Variant chr1-33013276-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00766 (1166/152232) while in subpopulation NFE AF = 0.0134 (914/68010). AF 95% confidence interval is 0.0127. There are 8 homozygotes in GnomAd4. There are 537 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

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.625G>A	p.Ala209Thr	missense	Exon 6 of 6	NP_001616.1	P54819-1
	AK2	NM_001319141.3		c.625G>A	p.Ala209Thr	missense	Exon 6 of 8	NP_001306070.1	F8W1A4
	AK2	NM_013411.5		c.625G>A	p.Ala209Thr	missense	Exon 6 of 7	NP_037543.1	P54819-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AK2	ENST00000672715.1	MANE Select	c.625G>A	p.Ala209Thr	missense	Exon 6 of 6	ENSP00000499935.1	P54819-1
	AK2	ENST00000373449.7	TSL:1	c.625G>A	p.Ala209Thr	missense	Exon 6 of 7	ENSP00000362548.2	P54819-2
	AK2	ENST00000354858.11	TSL:1	c.499G>A	p.Ala167Thr	missense	Exon 5 of 5	ENSP00000346921.7	A0A5K1VW67

Frequencies

GnomAD3 genomes AF: 0.00767 AC: 1166 AN: 152114 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00714 AC: 1796 AN: 251440 AF XY: 0.00745

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00693

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.00603

GnomAD4 exome AF: 0.0125 AC: 18293 AN: 1461860 Hom.: 126 Cov.: 34 AF XY: 0.0124 AC XY: 9010 AN XY: 727232

African (AFR) AF: 0.00209 AC: 70 AN: 33480

American (AMR) AF: 0.00295 AC: 132 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00265 AC: 229 AN: 86258

European-Finnish (FIN) AF: 0.00631 AC: 337 AN: 53418

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.0151 AC: 16752 AN: 1111980

Other (OTH) AF: 0.0120 AC: 726 AN: 60396

GnomAD4 genome AF: 0.00766 AC: 1166 AN: 152232 Hom.: 8 Cov.: 32 AF XY: 0.00722 AC XY: 537 AN XY: 74420

African (AFR) AF: 0.00231 AC: 96 AN: 41544

American (AMR) AF: 0.00288 AC: 44 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4816

European-Finnish (FIN) AF: 0.00764 AC: 81 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 914 AN: 68010

Other (OTH) AF: 0.00521 AC: 11 AN: 2110

Alfa AF: 0.00982 Hom.: 16

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0133 AC: 114

ExAC AF: 0.00740 AC: 898

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0123

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)
-	-	1	Reticular dysgenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0093	T
Eigen	Benign	0.0048
Eigen_PC	Benign	0.089
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.23
Sift	Benign	0.43	T
Sift4G	Benign	0.56	T
Polyphen		0.89	P
Vest4		0.27
MVP		0.74
MPC		0.18
ClinPred		0.020	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.45
Mutation Taster		=80/20	polymorphism

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

Other links and lift over

dbSNP: rs12116440; hg19: chr1-33478877;