1-33013240-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001625.4(AK2):c.661G>A(p.Ala221Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000787 in 1,613,684 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000079 ( 1 hom. )

Consequence

AK2
NM_001625.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.15

Variant links:

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 links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05764398).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AK2	NM_001625.4 linkuse as main transcript	c.661G>A	p.Ala221Thr	missense_variant	6/6	ENST00000672715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AK2	ENST00000672715.1 linkuse as main transcript	c.661G>A	p.Ala221Thr	missense_variant	6/6		NM_001625.4	P3	P54819-1
	ENST00000427524.1 linkuse as main transcript	n.246-17795C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152124

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000660

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251462

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00115

Gnomad NFE exome

AF:

0.0000879

Gnomad OTH exome

AF:

0.000652

GnomAD4 exome

AF:

0.0000794

AC:

116

AN:

1461560

Hom.:

Cov.:

AF XY:

0.0000756

AC XY:

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00146

Gnomad4 NFE exome

AF:

0.0000216

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152124

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000660

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000140

Hom.:

ExAC

AF:

0.000181

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.661G>A (p.A221T) alteration is located in exon 6 (coding exon 6) of the AK2 gene. This alteration results from a G to A substitution at nucleotide position 661, causing the alanine (A) at amino acid position 221 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Reticular dysgenesis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 06, 2021

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with AK2-related conditions. This variant is present in population databases (rs201817938, ExAC 0.2%). This sequence change replaces alanine with threonine at codon 221 of the AK2 protein (p.Ala221Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Benign

-0.14

Cadd

Benign

Dann

Uncertain

0.99

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.0029

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Benign

0.058

MetaRNN

Benign

0.058

T;T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Uncertain

2.7

M;.;.;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.97

N;N;N;N

REVEL

Benign

0.24

Sift

Benign

0.18

T;T;T;T

Sift4G

Benign

0.36

T;T;T;T

Polyphen

0.0030

B;B;.;B

Vest4

0.50

MutPred

0.37

Loss of catalytic residue at A221 (P = 0.1868);.;Loss of catalytic residue at A221 (P = 0.1868);Loss of catalytic residue at A221 (P = 0.1868);

MVP

0.69

MPC

0.18

ClinPred

0.15

GERP RS

4.3

Varity_R

0.25

gMVP

0.39

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over