rs141772938

chr22-41507837-C-Gchr22-41507837-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong 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:2 U:7 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 -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, ACO2
• BP4: Computational evidence support a benign effect (MetaRNN=0.018066943).
• BS2: High Homozygotes in GnomAdExome at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACO2	NM_001098.3	c.220C>G	p.Leu74Val	missense_variant	3/18	ENST00000216254.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACO2	ENST00000216254.9	c.220C>G	p.Leu74Val	missense_variant	3/18	1	NM_001098.3	P3

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:2 Uncertain:7 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ACO2: BP5, BS2 -
Likely pathogenic, flagged submission	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 03, 2023	Functional data demonstrated that the mutant protein failed to rescue mitochondrial aconitase deficient yeast strain (Metodiev et al., 2014); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 28463998, 29577077, 34056600, 31106992, 30689204, 31765440, 32519519, 34426522, 34354088, 34234304, 25351951, 32449285, 30831606, 30118607) -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -

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

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -

OPTIC ATROPHY 9, AUTOSOMAL RECESSIVE Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2014

- -

Optic atrophy 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Jun 23, 2022

- -

ACO2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 26, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

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;.
MutationTaster	Benign	1.0	D;D
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;