22-41469330-G-A

Position:

• chr22-41469330-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001098.3(ACO2):​c.36+148G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0399 in 928,594 control chromosomes in the GnomAD database, including 947 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.031 (123 hom., cov: 32)
  • Exomes 𝑓: 0.042 (824 hom.)
• Consequence: ACO2 NM_001098.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.18

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 22-41469330-G-A is Benign according to our data. Variant chr22-41469330-G-A is described in ClinVar as [Benign]. Clinvar id is 1252576.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO2	NM_001098.3	c.36+148G>A		intron_variant		ENST00000216254.9	NP_001089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACO2	ENST00000216254.9	c.36+148G>A		intron_variant		1	NM_001098.3	ENSP00000216254	P3

Frequencies

GnomAD3 genomes AF: 0.0312 AC: 4745 AN: 152188 Hom.: 124 Cov.: 32

Gnomad AFR AF: 0.00827

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0226

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.0218

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0528

Gnomad OTH AF: 0.0382

GnomAD4 exome AF: 0.0416 AC: 32287 AN: 776288 Hom.: 824 Cov.: 10 AF XY: 0.0407 AC XY: 15960 AN XY: 392474

Gnomad4 AFR exome AF: 0.00734

Gnomad4 AMR exome AF: 0.0216

Gnomad4 ASJ exome AF: 0.0308

Gnomad4 EAS exome AF: 0.000141

Gnomad4 SAS exome AF: 0.00541

Gnomad4 FIN exome AF: 0.0261

Gnomad4 NFE exome AF: 0.0499

Gnomad4 OTH exome AF: 0.0376

GnomAD4 genome AF: 0.0311 AC: 4744 AN: 152306 Hom.: 123 Cov.: 32 AF XY: 0.0283 AC XY: 2110 AN XY: 74478

Gnomad4 AFR AF: 0.00825

Gnomad4 AMR AF: 0.0226

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00498

Gnomad4 FIN AF: 0.0218

Gnomad4 NFE AF: 0.0529

Gnomad4 OTH AF: 0.0378

Alfa AF: 0.0451 Hom.: 23

Bravo AF: 0.0309

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs117369326; hg19: chr22-41865334;