22-41518589-C-T

Variant names:

• chr22-41518589-C-T
• rs203319
• NM_001098.3:c.1032+17C>T

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.26
• Publications: 21 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=-0.86).
• 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.

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.1032+17C>T		intron	N/A	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.1032+17C>T		intron	N/A	ENSP00000216254.4	Q99798
	ACO2	ENST00000878390.1		c.1032+17C>T		intron	N/A	ENSP00000548449.1
	ACO2	ENST00000878384.1		c.1032+17C>T		intron	N/A	ENSP00000548443.1

Frequencies

GnomAD3 genomes AF: 0.352 AC: 53440 AN: 151762 Hom.: 11381 Cov.: 31

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

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.: 26 AF XY: 0.253 AC XY: 182158 AN XY: 719894

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

GnomAD4 genome AF: 0.352 AC: 53531 AN: 151880 Hom.: 11416 Cov.: 31 AF XY: 0.360 AC XY: 26762 AN XY: 74248

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: 92 AN: 292

European-Non Finnish (NFE) AF: 0.203 AC: 13788 AN: 67948

Other (OTH) AF: 0.347 AC: 732 AN: 2112

Alfa AF: 0.239 Hom.: 1528

Bravo AF: 0.384

Asia WGS AF: 0.417 AC: 1448 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	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	-0.86
CADD	Benign	0.76
DANN	Benign	0.58
PhyloP100		-1.3
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: rs203319; hg19: chr22-41914593;