rs137831

Positions:

• chr22-41507809-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000216254.9(ACO2):​c.192A>C​(p.Thr64=) 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 ENST00000216254.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.883

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 128256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41507809-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO2	NM_001098.3	c.192A>C	p.Thr64=	synonymous_variant	3/18	ENST00000216254.9	NP_001089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACO2	ENST00000216254.9	c.192A>C	p.Thr64=	synonymous_variant	3/18	1	NM_001098.3	ENSP00000216254	P3

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

GnomAD3 exomes AF: 0.334 AC: 83458 AN: 249530 Hom.: 17715 AF XY: 0.323 AC XY: 43582 AN XY: 135104

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 SAS exome AF: 0.374

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

Gnomad4 AFR exome AF: 0.368

Gnomad4 AMR exome AF: 0.626

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.456

Gnomad4 SAS exome AF: 0.376

Gnomad4 FIN exome AF: 0.258

Gnomad4 NFE exome AF: 0.203

Gnomad4 OTH exome AF: 0.278

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

Gnomad4 AFR AF: 0.357

Gnomad4 AMR AF: 0.472

Gnomad4 ASJ AF: 0.296

Gnomad4 EAS AF: 0.535

Gnomad4 SAS AF: 0.403

Gnomad4 FIN AF: 0.261

Gnomad4 NFE AF: 0.202

Gnomad4 OTH AF: 0.310

Alfa AF: 0.233 Hom.: 6664

Bravo AF: 0.321

Asia WGS AF: 0.398 AC: 1380 AN: 3472

EpiCase AF: 0.224

EpiControl AF: 0.215

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -

Optic atrophy 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Infantile cerebellar-retinal degeneration Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.8
DANN	Benign	0.39

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

Publications

LitVar

Other links and lift over

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