17-42844831-C-T

Variant names:

• chr17-42844831-C-T
• rs150378203
• NM_009590.4:c.205C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_009590.4(AOC2):​c.205C>T​(p.Arg69Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,612,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R69H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00049 (0 hom.)
• Consequence: AOC2 NM_009590.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.389

Genes affected

AOC2 (HGNC:549): (amine oxidase copper containing 2) Copper amine oxidases catalyze the oxidative conversion of amines to aldehydes and ammonia in the presence of copper and quinone cofactor. This gene shows high sequence similarity to copper amine oxidases from various species ranging from bacteria to mammals. The protein contains several conserved motifs including the active site of amine oxidases and the histidine residues that likely bind copper. It may be a critical modulator of signal transmission in retina, possibly by degrading the biogenic amines dopamine, histamine, and putrescine. This gene may be a candidate gene for hereditary ocular diseases. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09478864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AOC2	NM_009590.4	c.205C>T	p.Arg69Cys	missense_variant	Exon 1 of 4	ENST00000253799.8	NP_033720.2
AOC2	NM_001158.5	c.205C>T	p.Arg69Cys	missense_variant	Exon 1 of 4		NP_001149.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AOC2	ENST00000253799.8	c.205C>T	p.Arg69Cys	missense_variant	Exon 1 of 4	1	NM_009590.4	ENSP00000253799.2
AOC2	ENST00000452774.2	c.205C>T	p.Arg69Cys	missense_variant	Exon 1 of 4	1		ENSP00000406134.1

Frequencies

GnomAD3 genomes AF: 0.000532 AC: 81 AN: 152198 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000438 AC: 110 AN: 250912 Hom.: 0 AF XY: 0.000457 AC XY: 62 AN XY: 135572

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.000399

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.000740

Gnomad NFE exome AF: 0.000573

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.000490 AC: 715 AN: 1460636 Hom.: 0 Cov.: 32 AF XY: 0.000482 AC XY: 350 AN XY: 726376

Gnomad4 AFR exome AF: 0.000150

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00103

Gnomad4 NFE exome AF: 0.000517

Gnomad4 OTH exome AF: 0.000647

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152316 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74466

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00107

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000784 Hom.: 0

Bravo AF: 0.000317

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.000412 AC: 50

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000545

EpiControl AF: 0.000415

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 17, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.205C>T (p.R69C) alteration is located in exon 1 (coding exon 1) of the AOC2 gene. This alteration results from a C to T substitution at nucleotide position 205, causing the arginine (R) at amino acid position 69 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.39
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.095	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.1	D;D
REVEL	Benign	0.14
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		0.99	D;D
Vest4		0.35
MVP		0.59
MPC		0.19
ClinPred		0.079	T
GERP RS		-3.2
Varity_R		0.22
gMVP		0.36

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: rs150378203; hg19: chr17-40996848;