1-33096815-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_052998.4(AZIN2):c.862G>T(p.Ala288Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00692 in 1,614,204 control chromosomes in the GnomAD database, including 567 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (73 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (494 hom.)
• Consequence: AZIN2 NM_052998.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 10.0

Genes affected

AZIN2 (HGNC:29957): (antizyme inhibitor 2) The protein encoded by this gene belongs to the antizyme inhibitor family, which plays a role in cell growth and proliferation by maintaining polyamine homeostasis within the cell. Antizyme inhibitors are homologs of ornithine decarboxylase (ODC, the key enzyme in polyamine biosynthesis) that have lost the ability to decarboxylase ornithine; however, retain the ability to bind to antizymes. Antizymes negatively regulate intracellular polyamine levels by binding to ODC and targeting it for degradation, as well as by inhibiting polyamine uptake. Antizyme inhibitors function as positive regulators of polyamine levels by sequestering antizymes and neutralizing their effect. This gene encodes antizyme inhibitor 2, the second member of this gene family. Like antizyme inhibitor 1, antizyme inhibitor 2 interacts with all 3 antizymes and stimulates ODC activity and polyamine uptake. However, unlike antizyme inhibitor 1, which is ubiquitously expressed and localized in the nucleus and cytoplasm, antizyme inhibitor 2 is predominantly expressed in the brain and testis and localized in the endoplasmic reticulum-golgi intermediate compartment. Recent studies indicate that antizyme inhibitor 2 is also expressed in specific cell types in ovaries, adrenal glands and pancreas, and in mast cells. The exact function of this gene is not known, however, available data suggest its role in cell growth, spermiogenesis, vesicular trafficking and secretion. Accumulation of antizyme inhibitor 2 has also been observed in brains of patients with Alzheimer's disease. There has been confusion in literature and databases over the nomenclature of this gene, stemming from an earlier report that a human cDNA clone (identical to ODCp/AZIN2) had arginine decarboxylase (ADC) activity (PMID:14738999). Subsequent studies in human and mouse showed that antizyme inhibitor 2 was devoid of arginine decarboxylase activity (PMID:19956990). Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Sep 2014]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024927258).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0924 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AZIN2	NM_052998.4	c.862G>T	p.Ala288Ser	missense_variant	9/12	ENST00000294517.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AZIN2	ENST00000294517.11	c.862G>T	p.Ala288Ser	missense_variant	9/12	1	NM_052998.4	P1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1688 AN: 152194 Hom.: 74 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0639

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.0998

Gnomad SAS AF: 0.00745

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000720

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0249 AC: 6251 AN: 251436 Hom.: 393 AF XY: 0.0199 AC XY: 2705 AN XY: 135888

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.00188

Gnomad EAS exome AF: 0.0992

Gnomad SAS exome AF: 0.00317

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.000791

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.00649 AC: 9494 AN: 1461892 Hom.: 494 Cov.: 31 AF XY: 0.00587 AC XY: 4272 AN XY: 727246

Gnomad4 AFR exome AF: 0.000627

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.00226

Gnomad4 EAS exome AF: 0.0791

Gnomad4 SAS exome AF: 0.00380

Gnomad4 FIN exome AF: 0.000300

Gnomad4 NFE exome AF: 0.000351

Gnomad4 OTH exome AF: 0.00979

GnomAD4 genome AF: 0.0110 AC: 1682 AN: 152312 Hom.: 73 Cov.: 32 AF XY: 0.0122 AC XY: 909 AN XY: 74474

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.0635

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.0995

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000720

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.00497 Hom.: 66

Bravo AF: 0.0174

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0204 AC: 2475

Asia WGS AF: 0.0400 AC: 139 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000711

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D;.;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0025	T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D;D;D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		0.28	B;B;D;P
Vest4		0.44
MPC		0.40
ClinPred		0.060	T
GERP RS		5.7
Varity_R		0.61
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs16835244; hg19: chr1-33562416;