22-41515521-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

37 publications found

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 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

ACO2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 128257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

GnomAD2 exomes

AF:

0.390

AC:

96698

AN:

247828

AF XY:

0.404

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 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

African (AFR)

AF:

0.143

AC:

4786

AN:

33388

American (AMR)

AF:

0.219

AC:

9712

AN:

44404

Ashkenazi Jewish (ASJ)

AF:

0.449

AC:

11620

AN:

25888

East Asian (EAS)

AF:

0.290

AC:

11521

AN:

39680

South Asian (SAS)

AF:

0.388

AC:

33347

AN:

85938

European-Finnish (FIN)

AF:

0.444

AC:

23660

AN:

53296

Middle Eastern (MID)

AF:

0.365

AC:

2088

AN:

5714

European-Non Finnish (NFE)

AF:

0.510

AC:

566563

AN:

1110468

Other (OTH)

AF:

0.429

AC:

25813

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

21070

42140

63211

84281

105351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16046

32092

48138

64184

80230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.367

AC:

55784

AN:

151812

Hom.:

12096

Cov.:

AF XY:

0.363

AC XY:

26924

AN XY:

74172

show subpopulations

African (AFR)

AF:

0.157

AC:

6505

AN:

41416

American (AMR)

AF:

0.307

AC:

4681

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.461

AC:

1601

AN:

3470

East Asian (EAS)

AF:

0.216

AC:

1111

AN:

5146

South Asian (SAS)

AF:

0.375

AC:

1803

AN:

4810

European-Finnish (FIN)

AF:

0.437

AC:

4599

AN:

10514

Middle Eastern (MID)

AF:

0.388

AC:

114

AN:

294

European-Non Finnish (NFE)

AF:

0.505

AC:

34255

AN:

67872

Other (OTH)

AF:

0.350

AC:

738

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

1576

3152

4729

6305

7881

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

536

1072

1608

2144

2680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.468

Hom.:

29633

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

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. -

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

- -

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

(source)

DANN

Benign

0.75

PhyloP100

3.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over