22-41469157-A-G

Variant names:

• chr22-41469157-A-G
• rs1432057983
• NM_001098.3:c.11A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001098.3(ACO2):​c.11A>G​(p.Tyr4Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,457,376 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: ACO2 NM_001098.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.03
• Publications: 4 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: Uncertain_significance. The variant received 0 ACMG points.

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.11A>G	p.Tyr4Cys	missense	Exon 1 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.11A>G	p.Tyr4Cys	missense	Exon 1 of 18	ENSP00000216254.4	Q99798
	ACO2	ENST00000677153.1		c.-304A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	ENSP00000504453.1	A0A7I2V586
	ACO2	ENST00000676792.1		c.-477A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	ENSP00000503590.1	A0A7I2V3U0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247242 AF XY: 0.00000747

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1457376 Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 725028

African (AFR) AF: 0.00 AC: 0 AN: 33120

American (AMR) AF: 0.00 AC: 0 AN: 44158

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39168

South Asian (SAS) AF: 0.00 AC: 0 AN: 85794

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1109892

Other (OTH) AF: 0.0000332 AC: 2 AN: 60168

GnomAD4 genome Cov.: 32

Alfa AF: 0.000223 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	M
PhyloP100		8.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.77	N
REVEL	Benign	0.18
Sift	Benign	0.043	D
Sift4G	Benign	0.069	T
Polyphen		0.53	P
Vest4		0.83
MutPred		0.42		Loss of disorder (P = 0.0708)
MVP		0.72
MPC		1.2
ClinPred		0.95	D
GERP RS		5.3
PromoterAI		0.063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.79
Mutation Taster		=58/42	polymorphism

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: rs1432057983; hg19: chr22-41865161; COSMIC: COSV53440450; COSMIC: COSV53440450;