Genetic Variant ACO2:p.Leu224Leu (chr22-41515521-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_001098.3(ACO2):c.670C>T(p.Leu224Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.462 in 1,610,822 control chromosomes in the GnomAD database, including 181,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.37 ( 12096 hom., cov: 31)

Exomes 𝑓: 0.47 ( 169463 hom. )

Consequence

ACO2
NM_001098.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 3.87

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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 22-41515521-C-T is Benign according to our data. Variant chr22-41515521-C-T is described in ClinVar as [Benign]. Clinvar id is 128257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41515521-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.5 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO2	NM_001098.3 link	c.670C>T	p.Leu224Leu	synonymous_variant	Exon 5 of 18	ENST00000216254.9	NP_001089.1	Q99798

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO2	ENST00000216254.9 link	c.670C>T	p.Leu224Leu	synonymous_variant	Exon 5 of 18	1	NM_001098.3	ENSP00000216254.4		Q99798

Frequencies

GnomAD3 genomes

AF:

0.368

AC:

55803

AN:

151694

Hom.:

12097

Cov.:

show subpopulations

Gnomad AFR

AF:

0.158

Gnomad AMI

AF:

0.413

Gnomad AMR

AF:

0.307

Gnomad ASJ

AF:

0.461

Gnomad EAS

AF:

0.216

Gnomad SAS

AF:

0.375

Gnomad FIN

AF:

0.437

Gnomad MID

AF:

0.389

Gnomad NFE

AF:

0.505

Gnomad OTH

AF:

0.355

GnomAD3 exomes

AF:

0.390

AC:

96698

AN:

247828

Hom.:

21305

AF XY:

0.404

AC XY:

54107

AN XY:

133954

show subpopulations

Gnomad AFR exome

AF:

0.157

Gnomad AMR exome

AF:

0.209

Gnomad ASJ exome

AF:

0.445

Gnomad EAS exome

AF:

0.177

Gnomad SAS exome

AF:

0.384

Gnomad FIN exome

AF:

0.441

Gnomad NFE exome

AF:

0.500

Gnomad OTH exome

AF:

0.415

GnomAD4 exome

AF:

0.472

AC:

689110

AN:

1459010

Hom.:

169463

Cov.:

AF XY:

0.472

AC XY:

342680

AN XY:

725664

show subpopulations

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.219

Gnomad4 ASJ exome

AF:

0.449

Gnomad4 EAS exome

AF:

0.290

Gnomad4 SAS exome

AF:

0.388

Gnomad4 FIN exome

AF:

0.444

Gnomad4 NFE exome

AF:

0.510

Gnomad4 OTH exome

AF:

0.429

GnomAD4 genome

AF:

0.367

AC:

55784

AN:

151812

Hom.:

12096

Cov.:

AF XY:

0.363

AC XY:

26924

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.157

Gnomad4 AMR

AF:

0.307

Gnomad4 ASJ

AF:

0.461

Gnomad4 EAS

AF:

0.216

Gnomad4 SAS

AF:

0.375

Gnomad4 FIN

AF:

0.437

Gnomad4 NFE

AF:

0.505

Gnomad4 OTH

AF:

0.350

Alfa

AF:

0.471

Hom.:

26043

Bravo

AF:

0.342

Asia WGS

AF:

0.278

AC:

969

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Sep 09, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

not provided

Benign:3

Feb 11, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Optic atrophy 9

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Infantile cerebellar-retinal degeneration

Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

9.8

DANN

Benign

0.75

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