22-41515521-C-G

Variant names:

• chr22-41515521-C-G
• rs1799932
• NM_001098.3:c.670C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001098.3(ACO2):​c.670C>G​(p.Leu224Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L224P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ACO2 NM_001098.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.87
• Publications: 37 publications found

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

ACMG classification

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, 0.889

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO2	NM_001098.3	c.670C>G	p.Leu224Val	missense_variant	Exon 5 of 18	ENST00000216254.9	NP_001089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO2	ENST00000216254.9	c.670C>G	p.Leu224Val	missense_variant	Exon 5 of 18	1	NM_001098.3	ENSP00000216254.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 29633

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.60	D;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Uncertain	2.3	M;.
PhyloP100		3.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.23
Sift	Benign	0.055	T;T
Sift4G	Uncertain	0.051	T;T
Polyphen		0.61	P;P
Vest4		0.77
MutPred		0.75		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.50
MPC		1.7
ClinPred		0.95	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.54
gMVP		0.79
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.34		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.34		Position offset: -1

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

Other links and lift over

dbSNP: rs1799932; hg19: chr22-41911525;