22-41515521-C-T

Variant names:

• chr22-41515521-C-T
• rs1799932
• NM_001098.3:c.670C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 3.87
• Publications: 37 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 -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.

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.670C>T	p.Leu224Leu	synonymous	Exon 5 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.670C>T	p.Leu224Leu	synonymous	Exon 5 of 18	ENSP00000216254.4	Q99798
	ACO2	ENST00000878390.1		c.670C>T	p.Leu224Leu	synonymous	Exon 5 of 20	ENSP00000548449.1
	ACO2	ENST00000878384.1		c.670C>T	p.Leu224Leu	synonymous	Exon 5 of 19	ENSP00000548443.1

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55803 AN: 151694 Hom.: 12097 Cov.: 31

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

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.: 65 AF XY: 0.472 AC XY: 342680 AN XY: 725664

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

GnomAD4 genome AF: 0.367 AC: 55784 AN: 151812 Hom.: 12096 Cov.: 31 AF XY: 0.363 AC XY: 26924 AN XY: 74172

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

Alfa AF: 0.468 Hom.: 29633

Bravo AF: 0.342

Asia WGS AF: 0.278 AC: 969 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (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	-0.41
CADD	Benign	9.8
DANN	Benign	0.75
PhyloP100		3.9
Mutation Taster		=100/0	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: rs1799932; hg19: chr22-41911525; COSMIC: COSV53441563; COSMIC: COSV53441563;