rs188233863

chr22-41499761-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001098.3(ACO2):c.72A>G(p.Ser24=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000332 in 1,613,636 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (2 hom.)
• Consequence: ACO2 NM_001098.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.15

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 22-41499761-A-G is Benign according to our data. Variant chr22-41499761-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 257431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-41499761-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.15 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACO2	NM_001098.3	c.72A>G	p.Ser24=	synonymous_variant	2/18	ENST00000216254.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACO2	ENST00000216254.9	c.72A>G	p.Ser24=	synonymous_variant	2/18	1	NM_001098.3	P3

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000207 AC: 52 AN: 251104 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135724

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000344 AC: 503 AN: 1461422 Hom.: 2 Cov.: 31 AF XY: 0.000344 AC XY: 250 AN XY: 727030

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000564

Gnomad4 NFE exome AF: 0.000429

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74384

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000398 Hom.: 0

Bravo AF: 0.000227

EpiCase AF: 0.000545

EpiControl AF: 0.000296

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2018	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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	ACO2: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	6.4
Dann	Benign	0.69

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: rs188233863; hg19: chr22-41895765;