3-58509024-T-C

Position:

• chr3-58509024-T-C

Variant summary

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

The NM_003500.4(ACOX2):​c.1852A>G​(p.Lys618Glu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACOX2 NM_003500.4 missense, splice_region
• Scores: Splicing: ADA: 0.7944
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.44

Genes affected

ACOX2 (HGNC:120): (acyl-CoA oxidase 2) The product of this gene belongs to the acyl-CoA oxidase family. It encodes the branched-chain acyl-CoA oxidase which is involved in the degradation of long branched fatty acids and bile acid intermediates in peroxisomes. Deficiency of this enzyme results in the accumulation of branched fatty acids and bile acid intermediates, and may lead to Zellweger syndrome, severe cognitive disability, and death in children. [provided by RefSeq, Mar 2009]

ACOX2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACOX2	NM_003500.4	c.1852A>G	p.Lys618Glu	missense_variant, splice_region_variant	14/15	ENST00000302819.10	NP_003491.1
ACOX2	XM_047449042.1	c.2050A>G	p.Lys684Glu	missense_variant, splice_region_variant	14/15		XP_047304998.1
ACOX2	XM_005265505.2	c.1852A>G	p.Lys618Glu	missense_variant, splice_region_variant	14/15		XP_005265562.1
ACOX2	XM_006713340.4	c.1558A>G	p.Lys520Glu	missense_variant, splice_region_variant	13/14		XP_006713403.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACOX2	ENST00000302819.10	c.1852A>G	p.Lys618Glu	missense_variant, splice_region_variant	14/15	1	NM_003500.4	ENSP00000307697.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.1852A>G (p.K618E) alteration is located in exon 14 (coding exon 13) of the ACOX2 gene. This alteration results from a A to G substitution at nucleotide position 1852, causing the lysine (K) at amino acid position 618 to be replaced by a glutamic acid (E). 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	0.10
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.54	T;T
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.55	D;D
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.9	.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.21
Sift	Benign	0.049	D;D
Sift4G	Benign	0.064	T;T
Polyphen		0.94	.;P
Vest4		0.53
MutPred		0.55		.;Loss of ubiquitination at K618 (P = 0.0341);
MVP		0.51
MPC		0.75
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.31
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.79
dbscSNV1_RF	Benign	0.72
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-58494751;