22-41507837-C-G

Variant names:

• chr22-41507837-C-G
• rs141772938
• NM_001098.3:c.220C>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BS1_Supporting BS2

The NM_001098.3(ACO2):​c.220C>G​(p.Leu74Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,614,196 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (26 hom.)
• Consequence: ACO2 NM_001098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:8 B:4 O:1
• Conservation: PhyloP100: 0.864

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 Benign. Variant got -8 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.018066943).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00362 (552/152372) while in subpopulation NFE AF= 0.0062 (422/68044). AF 95% confidence interval is 0.00571. There are 1 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO2	NM_001098.3	c.220C>G	p.Leu74Val	missense_variant	Exon 3 of 18	ENST00000216254.9	NP_001089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO2	ENST00000216254.9	c.220C>G	p.Leu74Val	missense_variant	Exon 3 of 18	1	NM_001098.3	ENSP00000216254.4

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 553 AN: 152254 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00370 AC: 929 AN: 250844 Hom.: 4 AF XY: 0.00377 AC XY: 511 AN XY: 135686

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00170

Gnomad FIN exome AF: 0.00324

Gnomad NFE exome AF: 0.00648

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00471 AC: 6886 AN: 1461824 Hom.: 26 Cov.: 33 AF XY: 0.00456 AC XY: 3317 AN XY: 727214

Gnomad4 AFR exome AF: 0.000747

Gnomad4 AMR exome AF: 0.000895

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.00369

Gnomad4 NFE exome AF: 0.00563

Gnomad4 OTH exome AF: 0.00341

GnomAD4 genome AF: 0.00362 AC: 552 AN: 152372 Hom.: 1 Cov.: 32 AF XY: 0.00352 AC XY: 262 AN XY: 74518

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00372

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00273

Gnomad4 NFE AF: 0.00620

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00462 Hom.: 1

Bravo AF: 0.00354

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00410 AC: 498

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00498

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:8 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:2 Uncertain:3 Benign:2

Feb 01, 2021

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACO2 p.Leu74Val variant was identified in the literature in two adult male siblings with optic atrophy beginning in childhood; the p.L74V variant was found as a compound heterozygous mutation with a ACO2 p.G661R variant. Decreased ACO2 protein levels were observed in fibroblasts from these two patients (Metodiev_2014_PMID:25351951). The variant was identified in dbSNP (ID: rs141772938) and ClinVar (classified as uncertain significance by Fulgent Genetics, GeneDx, EGL Genetics and Mayo Clinic, and as likely pathogenic by CeGaT Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 1055 of 282256 chromosomes (4 homozygous) at a frequency of 0.003738 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 839 of 128790 chromosomes (freq: 0.006514), Other in 30 of 7208 chromosomes (freq: 0.004162), European (Finnish) in 80 of 25082 chromosomes (freq: 0.00319), South Asian in 52 of 30602 chromosomes (freq: 0.001699), African in 23 of 24894 chromosomes (freq: 0.000924) and Latino in 31 of 35394 chromosomes (freq: 0.000876), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Leu74 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACO2: BS2 -

Oct 12, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 26, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2025

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Functional data demonstrated that the mutant protein failed to rescue mitochondrial aconitase deficient yeast strain (PMID: 25351951); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28463998, 29577077, 34056600, 31106992, 30689204, 31765440, 32519519, 34426522, 34354088, 34234304, 25351951, 32449285, 30831606, 30118607, 38007539, 37734845, 38796496, 39462066, 39337438) -

Infantile cerebellar-retinal degeneration;C4225384:Optic atrophy 9 Uncertain:1 Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant identified in multiple GenomeConnect participants. Variant classified, most recently, as Uncertain significance and reported on 01-02-2020 by Lab or GTR ID 26957. Variant previously reported as a "disease-causing mutation" by GTR ID 26957 in April 2015. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

OPTIC ATROPHY 9, AUTOSOMAL RECESSIVE Pathogenic:1

Dec 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Optic atrophy Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Optic atrophy 9 Uncertain:1

Jun 23, 2022

MGZ Medical Genetics Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Retinal dystrophy Uncertain:1

Jan 01, 2023

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

ACO2-related disorder Uncertain:1

Nov 29, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ACO2 c.220C>G variant is predicted to result in the amino acid substitution p.Leu74Val. This variant has been reported several times in the compound heterozygous state in individuals affected with optic atrophy and has been found to segregate with disease in the cases of multiple affected family members (Metodiev et al. 2014. PubMed ID: 25351951; Kelman et al. 2018. PubMed ID: 30118607; Benkirane et al. 2021. PubMed ID: 34234304; Charif et al. 2021. PubMed ID: 34056600). In many of the reported cases, this variant was found in combination with a loss-of-function variant suggesting the p.Leu74Val substitution has a mild effect on the encoded protein (Charif et al. 2021. PubMed ID: 34056600). Functional studies suggest that this variant may alter stability of the protein (Metodiev et al. 2014. PubMed ID: 25351951). However, this variant has also been reported at frequencies up to ~0.7%, including four homozygotes in a large population database. This variant also has conflicting interpretations of pathogenicity in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/189310/). Currently, we suspect that this variant is pathogenic and represents a mildly hypomorphic allele; however, at this time, the clinical significance of this variant is uncertain due to the conflicting functional and genetic evidence. -

not specified Benign:1

Jan 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ACO2 c.220C>G (p.Leu74Val) results in a conservative amino acid change located in the Aconitase/3-isopropylmalate dehydratase large subunit, alpha/beta/alpha domain (IPR001030) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0037 in 250844 control chromosomes in the gnomAD database, including 4 homozygotes. c.220C>G has been reported in the literature in individuals affected with isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy (Metodiev_2014, Benkirane_2021, Charif_2021). These reports do not provide unequivocal conclusions about association of the variant with ACO2-Related Disorders. At least one publication reports experimental evidence evaluating an impact on protein function and this variant was unable to complement the growth defect in yeast model (Metodiev_2014). The following publications have been ascertained in the context of this evaluation (PMID: 34234304, 34056600, 25351951). ClinVar contains an entry for this variant (Variation ID: 189310). Based on the evidence outlined above, the variant was classified as likely benign. -

Infantile cerebellar-retinal degeneration Benign:1

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.018	T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.5	M;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.55	P;P
Vest4		0.74
MVP		0.50
MPC		0.86
ClinPred		0.11	T
GERP RS		2.5
Varity_R		0.52
gMVP		0.65

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: rs141772938; hg19: chr22-41903841;