NM_001625.4:c.571C>G

Variant names:

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS1

The NM_001625.4(AK2):c.571C>G(p.His191Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00311 in 145,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0084 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AK2
NM_001625.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 9.96

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:

ENSG00000236065 (HGNC:):

ENSG00000236065 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -15 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, phyloP100way_vertebrate, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.004391223).

BP6

Variant 1-33013330-G-C is Benign according to our data. Variant chr1-33013330-G-C is described in ClinVar as [Benign]. Clinvar id is 529737.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 = 0.00311 (452/145184) while in subpopulation NFE AF= 0.00511 (333/65202). AF 95% confidence interval is 0.00466. There are 0 homozygotes in gnomad4. There are 292 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AK2	NM_001625.4 link	c.571C>G	p.His191Asp	missense_variant	Exon 6 of 6	ENST00000672715.1	NP_001616.1	P54819-1A0A140VK93

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AK2	ENST00000672715.1 link	c.571C>G	p.His191Asp	missense_variant	Exon 6 of 6		NM_001625.4	ENSP00000499935.1		P54819-1

Frequencies

GnomAD3 genomes

AF:

0.00310

AC:

450

AN:

145098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000962

Gnomad AMI

AF:

0.00112

Gnomad AMR

AF:

0.00179

Gnomad ASJ

AF:

0.00419

Gnomad EAS

AF:

0.00262

Gnomad SAS

AF:

0.00155

Gnomad FIN

AF:

0.000405

Gnomad MID

AF:

0.00325

Gnomad NFE

AF:

0.00511

Gnomad OTH

AF:

0.00656

GnomAD3 exomes

AF:

0.0346

AC:

5457

AN:

157516

Hom.:

AF XY:

0.0353

AC XY:

2935

AN XY:

83138

show subpopulations

Gnomad AFR exome

AF:

0.0514

Gnomad AMR exome

AF:

0.0241

Gnomad ASJ exome

AF:

0.0184

Gnomad EAS exome

AF:

0.0262

Gnomad SAS exome

AF:

0.0179

Gnomad FIN exome

AF:

0.0310

Gnomad NFE exome

AF:

0.0454

Gnomad OTH exome

AF:

0.0337

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00840

AC:

10081

AN:

1200458

Hom.:

Cov.:

AF XY:

0.00919

AC XY:

5500

AN XY:

598208

show subpopulations

Gnomad4 AFR exome

AF:

0.0102

Gnomad4 AMR exome

AF:

0.0294

Gnomad4 ASJ exome

AF:

0.00573

Gnomad4 EAS exome

AF:

0.0155

Gnomad4 SAS exome

AF:

0.00942

Gnomad4 FIN exome

AF:

0.0174

Gnomad4 NFE exome

AF:

0.00677

Gnomad4 OTH exome

AF:

0.00840

GnomAD4 genome

AF:

0.00311

AC:

452

AN:

145184

Hom.:

Cov.:

AF XY:

0.00414

AC XY:

292

AN XY:

70516

show subpopulations

Gnomad4 AFR

AF:

0.000984

Gnomad4 AMR

AF:

0.00186

Gnomad4 ASJ

AF:

0.00419

Gnomad4 EAS

AF:

0.00283

Gnomad4 SAS

AF:

0.00133

Gnomad4 FIN

AF:

0.000405

Gnomad4 NFE

AF:

0.00511

Gnomad4 OTH

AF:

0.00651

Alfa

AF:

0.156

Hom.:

ExAC

AF:

0.320

AC:

38814

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Reticular dysgenesis

Benign:1

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

.;D;D;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.71

T;T;T;T

MetaRNN

Benign

0.0044

T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.8

L;.;.;L

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-8.6

D;D;D;D

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.015

D;D;D;D

Polyphen

0.63

P;D;.;P

Vest4

0.32

MPC

0.88

ClinPred

0.056

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.79

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