22-41471373-C-T

Variant names:

• chr22-41471373-C-T
• rs727563
• NM_001098.3:c.36+2191C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000216254.9(ACO2):​c.36+2191C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.593 in 150,844 control chromosomes in the GnomAD database, including 29,711 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.59 (29711 hom., cov: 31)
• Consequence: ACO2 ENST00000216254.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.786
• Publications: 39 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: 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.774 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000216254.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	NM_001098.3	MANE Select	c.36+2191C>T		intron	N/A	NP_001089.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	ENST00000216254.9	TSL:1 MANE Select	c.36+2191C>T		intron	N/A	ENSP00000216254.4
	ACO2	ENST00000396512.3	TSL:5	c.36+2191C>T		intron	N/A	ENSP00000379769.3
	ACO2	ENST00000678269.1		c.36+2191C>T		intron	N/A	ENSP00000504150.1

Frequencies

GnomAD3 genomes AF: 0.593 AC: 89438 AN: 150724 Hom.: 29711 Cov.: 31

Gnomad AFR AF: 0.298

Gnomad AMI AF: 0.639

Gnomad AMR AF: 0.485

Gnomad ASJ AF: 0.687

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.581

Gnomad FIN AF: 0.733

Gnomad MID AF: 0.678

Gnomad NFE AF: 0.780

Gnomad OTH AF: 0.612

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.593 AC: 89433 AN: 150844 Hom.: 29711 Cov.: 31 AF XY: 0.586 AC XY: 43236 AN XY: 73764

African (AFR) AF: 0.297 AC: 12239 AN: 41202

American (AMR) AF: 0.484 AC: 7307 AN: 15086

Ashkenazi Jewish (ASJ) AF: 0.687 AC: 2364 AN: 3440

East Asian (EAS) AF: 0.473 AC: 2443 AN: 5170

South Asian (SAS) AF: 0.580 AC: 2790 AN: 4810

European-Finnish (FIN) AF: 0.733 AC: 7719 AN: 10530

Middle Eastern (MID) AF: 0.682 AC: 199 AN: 292

European-Non Finnish (NFE) AF: 0.780 AC: 52515 AN: 67332

Other (OTH) AF: 0.616 AC: 1296 AN: 2104

Alfa AF: 0.680 Hom.: 22759

Bravo AF: 0.553

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	9.3
DANN	Benign	0.48
PhyloP100		0.79
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: rs727563; hg19: chr22-41867377;