rs786204828

Variant names:

• chr22-41515858-G-A
• rs786204828
• NM_001098.3:c.776G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP2 PP3_Strong PP5

The NM_001098.3(ACO2):​c.776G>A​(p.Gly259Asp) 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 Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ACO2 NM_001098.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.31

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the ACO2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 37 curated benign missense variants. Gene score misZ: 2.9201 (below the threshold of 3.09). Trascript score misZ: 4.3251 (above the threshold of 3.09). GenCC associations: The gene is linked to infantile cerebellar-retinal degeneration, autosomal recessive optic atrophy, optic atrophy 9.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.968
• PP5: Variant 22-41515858-G-A is Pathogenic according to our data. Variant chr22-41515858-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 189312.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr22-41515858-G-A is described in Lovd as [Likely_pathogenic]. Variant chr22-41515858-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO2	NM_001098.3	c.776G>A	p.Gly259Asp	missense_variant	Exon 6 of 18	ENST00000216254.9	NP_001089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO2	ENST00000216254.9	c.776G>A	p.Gly259Asp	missense_variant	Exon 6 of 18	1	NM_001098.3	ENSP00000216254.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Infantile cerebellar-retinal degeneration Pathogenic:1

Dec 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.99
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.85	T;T
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-6.8	D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.89		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP		0.91
MPC		1.9
ClinPred		1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs786204828; hg19: chr22-41911862;