Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001098.3(ACO2):c.1397A>C(p.Asn466Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

ACO2
NM_001098.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.95

Publications

0 publications found

Variant links:

Genes affected

ACO2 (HGNC:118): (aconitase 2) The protein encoded by this gene belongs to the aconitase/IPM isomerase family. It is an enzyme that catalyzes the interconversion of citrate to isocitrate via cis-aconitate in the second step of the TCA cycle. This protein is encoded in the nucleus and functions in the mitochondrion. It was found to be one of the mitochondrial matrix proteins that are preferentially degraded by the serine protease 15(PRSS15), also known as Lon protease, after oxidative modification. [provided by RefSeq, Jul 2008]

ACO2 Gene-Disease associations (from GenCC):

infantile cerebellar-retinal degeneration
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
optic atrophy 9
Inheritance: Unknown, AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
autosomal recessive optic atrophy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACO2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.862

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098.3. 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
	ACO2	NM_001098.3	MANE Select	c.1397A>C	p.Asn466Thr	missense	Exon 12 of 18	NP_001089.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ACO2	ENST00000216254.9	TSL:1 MANE Select	c.1397A>C	p.Asn466Thr	missense	Exon 12 of 18	ENSP00000216254.4
ACO2	ENST00000396512.3	TSL:5	c.1472A>C	p.Asn491Thr	missense	Exon 12 of 18	ENSP00000379769.3
ACO2	ENST00000678269.1		c.1472A>C	p.Asn491Thr	missense	Exon 12 of 18	ENSP00000504150.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Neurodegeneration;C0557874:Global developmental delay;C1850456:Progressive microcephaly;C3805839:Central hypoventilation;C4551584:Brain atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.60

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.059

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

-0.089

MutationAssessor

Pathogenic

3.0

PhyloP100

8.9

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.52

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.023

Polyphen

1.0

Vest4

0.83

MutPred

0.63

Gain of sheet (P = 0.039)

MVP

0.83

MPC

1.7

ClinPred

1.0

GERP RS

5.2

Varity_R

0.91

gMVP

0.91

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs1057518831

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over