chr1-33013330-G-C

Position:

• chr1-33013330-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP4_Strong BP6_Very_Strong BS1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 9.96

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]

ENSG00000236065 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
AK2	NM_001625.4	c.571C>G	p.His191Asp	missense_variant	6/6	ENST00000672715.1	NP_001616.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AK2	ENST00000672715.1	c.571C>G	p.His191Asp	missense_variant	6/6		NM_001625.4	ENSP00000499935.1

Frequencies

GnomAD3 genomes AF: 0.00310 AC: 450 AN: 145098 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.0353 AC XY: 2935 AN XY: 83138

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.: 0 Cov.: 37 AF XY: 0.00919 AC XY: 5500 AN XY: 598208

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.: 0 Cov.: 32 AF XY: 0.00414 AC XY: 292 AN XY: 70516

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.: 0

ExAC AF: 0.320 AC: 38814

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Reticular dysgenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	30
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	D
LIST_S2	Benign	0.71	T;T;T;T
MetaRNN	Benign	0.0044	T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.8	L;.;.;L
PrimateAI	Uncertain	0.61	T
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	T
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

Other links and lift over

dbSNP: rs80324279; hg19: chr1-33478931; COSMIC: COSV61466144; COSMIC: COSV61466144;