chr1-33093391-C-A

Position:

• chr1-33093391-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_052998.4(AZIN2):​c.562C>A​(p.His188Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00524 in 1,613,952 control chromosomes in the GnomAD database, including 364 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.026 (188 hom., cov: 31)
  • Exomes 𝑓: 0.0030 (176 hom.)
• Consequence: AZIN2 NM_052998.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.45

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016043782).
• BP6: Variant 1-33093391-C-A is Benign according to our data. Variant chr1-33093391-C-A is described in ClinVar as [Benign]. Clinvar id is 770112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AZIN2	NM_052998.4	c.562C>A	p.His188Asn	missense_variant	7/12	ENST00000294517.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AZIN2	ENST00000294517.11	c.562C>A	p.His188Asn	missense_variant	7/12	1	NM_052998.4	P1

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 4015 AN: 152090 Hom.: 188 Cov.: 31

Gnomad AFR AF: 0.0913

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00903

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0225

GnomAD3 exomes AF: 0.00752 AC: 1888 AN: 251146 Hom.: 67 AF XY: 0.00557 AC XY: 756 AN XY: 135758

Gnomad AFR exome AF: 0.0975

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000484

Gnomad OTH exome AF: 0.00571

GnomAD4 exome AF: 0.00303 AC: 4427 AN: 1461744 Hom.: 176 Cov.: 30 AF XY: 0.00261 AC XY: 1897 AN XY: 727192

Gnomad4 AFR exome AF: 0.0983

Gnomad4 AMR exome AF: 0.00557

Gnomad4 ASJ exome AF: 0.00325

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000243

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000299

Gnomad4 OTH exome AF: 0.00707

GnomAD4 genome AF: 0.0265 AC: 4028 AN: 152208 Hom.: 188 Cov.: 31 AF XY: 0.0265 AC XY: 1972 AN XY: 74412

Gnomad4 AFR AF: 0.0913

Gnomad4 AMR AF: 0.00902

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.00516 Hom.: 54

Bravo AF: 0.0303

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.0917 AC: 404

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00922 AC: 1119

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000771

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 31, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.0094	.;T;T
MetaRNN	Benign	0.0016	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.97	D;D;N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.11	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.034	D;D;D
Sift4G	Uncertain	0.052	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.19
MVP		0.030
MPC		0.15
ClinPred		0.0071	T
GERP RS		0.49
Varity_R		0.064
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80137217; hg19: chr1-33558992;