1-33096815-G-T

Variant names:

• chr1-33096815-G-T
• rs16835244
• NM_052998.4:c.862G>T

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 8 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_052998.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AZIN2	NM_052998.4	MANE Select	c.862G>T	p.Ala288Ser	missense	Exon 9 of 12	NP_443724.1
	AZIN2	NM_001301825.1		c.862G>T	p.Ala288Ser	missense	Exon 6 of 9	NP_001288754.1
	AZIN2	NM_001293562.2		c.862G>T	p.Ala288Ser	missense	Exon 8 of 11	NP_001280491.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AZIN2	ENST00000294517.11	TSL:1 MANE Select	c.862G>T	p.Ala288Ser	missense	Exon 9 of 12	ENSP00000294517.6
	AZIN2	ENST00000373441.1	TSL:1	c.862G>T	p.Ala288Ser	missense	Exon 6 of 9	ENSP00000362540.1
	AZIN2	ENST00000373443.7	TSL:1	c.862G>T	p.Ala288Ser	missense	Exon 8 of 11	ENSP00000362542.3

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

GnomAD2 exomes AF: 0.0249 AC: 6251 AN: 251436 AF XY: 0.0199

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 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

African (AFR) AF: 0.000627 AC: 21 AN: 33480

American (AMR) AF: 0.111 AC: 4945 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00226 AC: 59 AN: 26136

East Asian (EAS) AF: 0.0791 AC: 3139 AN: 39700

South Asian (SAS) AF: 0.00380 AC: 328 AN: 86258

European-Finnish (FIN) AF: 0.000300 AC: 16 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.000351 AC: 390 AN: 1112010

Other (OTH) AF: 0.00979 AC: 591 AN: 60396

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

African (AFR) AF: 0.00152 AC: 63 AN: 41564

American (AMR) AF: 0.0635 AC: 972 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3468

East Asian (EAS) AF: 0.0995 AC: 515 AN: 5178

South Asian (SAS) AF: 0.00746 AC: 36 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000720 AC: 49 AN: 68034

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.00601 Hom.: 141

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 v4.9

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
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.84	T
PhyloP100		10
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.28	B
Vest4		0.44
MPC		0.40
ClinPred		0.060	T
GERP RS		5.7
Varity_R		0.61
gMVP		0.40
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16835244; hg19: chr1-33562416;