rs141772938

Positions:

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:6B:4O:1

Conservation

PhyloP100: 0.864

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -7 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACO2. . Gene score misZ 2.9201 (greater than the threshold 3.09). Trascript score misZ 4.3251 (greater than threshold 3.09). GenCC has associacion of gene with infantile cerebellar-retinal degeneration, autosomal recessive optic atrophy, optic atrophy 9.

BP4

Computational evidence support a benign effect (MetaRNN=0.018066943).

BS2

High Homozygotes in GnomAdExome4 at 26 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO2	NM_001098.3 linkuse as main transcript	c.220C>G	p.Leu74Val	missense_variant	3/18	ENST00000216254.9	NP_001089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACO2	ENST00000216254.9 linkuse as main transcript	c.220C>G	p.Leu74Val	missense_variant	3/18	1	NM_001098.3	ENSP00000216254	P3

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

553

AN:

152254

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00377

AC XY:

511

AN XY:

135686

show subpopulations

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.:

Cov.:

AF XY:

0.00456

AC XY:

3317

AN XY:

727214

show subpopulations

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.:

Cov.:

AF XY:

0.00352

AC XY:

262

AN XY:

74518

show subpopulations

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.:

Bravo

AF:

0.00354

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00547

AC:

ExAC

AF:

0.00410

AC:

498

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00458

EpiControl

AF:

0.00498

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:6Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:3Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely pathogenic, flagged submission	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Feb 01, 2021	- -
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 -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 12, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 26, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2024	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) -

Infantile cerebellar-retinal degeneration;C4225384:Optic atrophy 9

Uncertain:1Other:1

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

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, no assertion criteria provided

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

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.

Eigen

Uncertain

0.32

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.91

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-0.69

MutationAssessor

Pathogenic

3.5

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.57

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over