rs137831

Variant names:

• chr22-41507809-A-C
• rs137831
• NM_001098.3:c.192A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001098.3(ACO2):​c.192A>C​(p.Thr64Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 1,613,368 control chromosomes in the GnomAD database, including 58,833 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7797 hom., cov: 32)
  • Exomes 𝑓: 0.24 (51036 hom.)
• Consequence: ACO2 NM_001098.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.883
• Publications: 46 publications found

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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• mitochondrial disease

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen
• optic atrophy 9

  Inheritance: AR, AD, Unknown, SD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• autosomal recessive optic atrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 22-41507809-A-C is Benign according to our data. Variant chr22-41507809-A-C is described in ClinVar as Benign. ClinVar VariationId is 128256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	NM_001098.3	MANE Select	c.192A>C	p.Thr64Thr	synonymous	Exon 3 of 18	NP_001089.1	Q99798

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	ENST00000216254.9	TSL:1 MANE Select	c.192A>C	p.Thr64Thr	synonymous	Exon 3 of 18	ENSP00000216254.4	Q99798
	ACO2	ENST00000878390.1		c.192A>C	p.Thr64Thr	synonymous	Exon 3 of 20	ENSP00000548449.1
	ACO2	ENST00000878384.1		c.192A>C	p.Thr64Thr	synonymous	Exon 3 of 19	ENSP00000548443.1

Frequencies

GnomAD3 genomes AF: 0.298 AC: 45179 AN: 151834 Hom.: 7779 Cov.: 32

Gnomad AFR AF: 0.356

Gnomad AMI AF: 0.328

Gnomad AMR AF: 0.471

Gnomad ASJ AF: 0.296

Gnomad EAS AF: 0.536

Gnomad SAS AF: 0.402

Gnomad FIN AF: 0.261

Gnomad MID AF: 0.310

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.314

GnomAD2 exomes AF: 0.334 AC: 83458 AN: 249530 AF XY: 0.323

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.647

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.573

Gnomad FIN exome AF: 0.259

Gnomad NFE exome AF: 0.205

Gnomad OTH exome AF: 0.312

GnomAD4 exome AF: 0.244 AC: 356759 AN: 1461416 Hom.: 51036 Cov.: 35 AF XY: 0.246 AC XY: 179127 AN XY: 726964

African (AFR) AF: 0.368 AC: 12320 AN: 33472

American (AMR) AF: 0.626 AC: 27981 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7795 AN: 26132

East Asian (EAS) AF: 0.456 AC: 18099 AN: 39674

South Asian (SAS) AF: 0.376 AC: 32459 AN: 86218

European-Finnish (FIN) AF: 0.258 AC: 13774 AN: 53366

Middle Eastern (MID) AF: 0.319 AC: 1837 AN: 5764

European-Non Finnish (NFE) AF: 0.203 AC: 225730 AN: 1111740

Other (OTH) AF: 0.278 AC: 16764 AN: 60372

GnomAD4 genome AF: 0.298 AC: 45241 AN: 151952 Hom.: 7797 Cov.: 32 AF XY: 0.308 AC XY: 22837 AN XY: 74250

African (AFR) AF: 0.357 AC: 14772 AN: 41424

American (AMR) AF: 0.472 AC: 7206 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 1026 AN: 3468

East Asian (EAS) AF: 0.535 AC: 2762 AN: 5158

South Asian (SAS) AF: 0.403 AC: 1935 AN: 4806

European-Finnish (FIN) AF: 0.261 AC: 2751 AN: 10548

Middle Eastern (MID) AF: 0.306 AC: 90 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13745 AN: 67962

Other (OTH) AF: 0.310 AC: 655 AN: 2110

Alfa AF: 0.241 Hom.: 9095

Bravo AF: 0.321

Asia WGS AF: 0.398 AC: 1380 AN: 3472

EpiCase AF: 0.224

EpiControl AF: 0.215

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Infantile cerebellar-retinal degeneration (1)
-	-	1	Optic atrophy 9 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.8
DANN	Benign	0.39
PhyloP100		0.88
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs137831; hg19: chr22-41903813; COSMIC: COSV53441661; COSMIC: COSV53441661;