22-41518589-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001098.3(ACO2):c.1032+17C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 1,596,706 control chromosomes in the GnomAD database, including 66,512 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.35 ( 11416 hom., cov: 31)

Exomes 𝑓: 0.25 ( 55096 hom. )

Consequence

ACO2
NM_001098.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -1.26

Publications

21 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 22-41518589-C-T is Benign according to our data. Variant chr22-41518589-C-T is described in ClinVar as Benign. ClinVar VariationId is 136263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACO2	NM_001098.3 link	c.1032+17C>T		intron_variant	Intron 8 of 17	ENST00000216254.9	NP_001089.1	Q99798

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACO2	ENST00000216254.9 link	c.1032+17C>T		intron_variant	Intron 8 of 17	1	NM_001098.3	ENSP00000216254.4		Q99798

Frequencies

GnomAD3 genomes

AF:

0.352

AC:

53440

AN:

151762

Hom.:

11381

Cov.:

show subpopulations

Gnomad AFR

AF:

0.545

Gnomad AMI

AF:

0.328

Gnomad AMR

AF:

0.492

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.534

Gnomad SAS

AF:

0.408

Gnomad FIN

AF:

0.258

Gnomad MID

AF:

0.318

Gnomad NFE

AF:

0.203

Gnomad OTH

AF:

0.350

GnomAD2 exomes

AF:

0.351

AC:

88002

AN:

250906

AF XY:

0.336

show subpopulations

Gnomad AFR exome

AF:

0.551

Gnomad AMR exome

AF:

0.657

Gnomad ASJ exome

AF:

0.317

Gnomad EAS exome

AF:

0.574

Gnomad FIN exome

AF:

0.259

Gnomad NFE exome

AF:

0.206

Gnomad OTH exome

AF:

0.323

GnomAD4 exome

AF:

0.251

AC:

363278

AN:

1444826

Hom.:

55096

Cov.:

AF XY:

0.253

AC XY:

182158

AN XY:

719894

show subpopulations

African (AFR)

AF:

0.561

AC:

18576

AN:

33132

American (AMR)

AF:

0.638

AC:

28481

AN:

44618

Ashkenazi Jewish (ASJ)

AF:

0.313

AC:

8149

AN:

25998

East Asian (EAS)

AF:

0.456

AC:

18066

AN:

39580

South Asian (SAS)

AF:

0.385

AC:

33074

AN:

85870

European-Finnish (FIN)

AF:

0.258

AC:

13712

AN:

53182

Middle Eastern (MID)

AF:

0.326

AC:

1863

AN:

5710

European-Non Finnish (NFE)

AF:

0.204

AC:

223805

AN:

1096940

Other (OTH)

AF:

0.294

AC:

17552

AN:

59796

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

10996

21992

32988

43984

54980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8314

16628

24942

33256

41570

<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:

0.352

AC:

53531

AN:

151880

Hom.:

11416

Cov.:

AF XY:

0.360

AC XY:

26762

AN XY:

74248

show subpopulations

African (AFR)

AF:

0.546

AC:

22582

AN:

41374

American (AMR)

AF:

0.493

AC:

7527

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

1069

AN:

3468

East Asian (EAS)

AF:

0.533

AC:

2747

AN:

5152

South Asian (SAS)

AF:

0.409

AC:

1971

AN:

4820

European-Finnish (FIN)

AF:

0.258

AC:

2724

AN:

10540

Middle Eastern (MID)

AF:

0.315

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.203

AC:

13788

AN:

67948

Other (OTH)

AF:

0.347

AC:

732

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1539

3079

4618

6158

7697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

496

992

1488

1984

2480

<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:

0.239

Hom.:

1528

Bravo

AF:

0.384

Asia WGS

AF:

0.417

AC:

1448

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 06, 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. -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.86

CADD

Benign

0.76

(source)

DANN

Benign

0.58

PhyloP100

-1.3

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