chr22-41526302-G-A

Position:

• chr22-41526302-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The ENST00000216254.9(ACO2):​c.1802G>A​(p.Gly601Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACO2 ENST00000216254.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.60

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]

POLR3H (HGNC:30349): (RNA polymerase III subunit H) Enables DNA-directed 5'-3' RNA polymerase activity. Involved in transcription by RNA polymerase III. Located in centrosome and nucleoplasm. Part of RNA polymerase III complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), ACO2. . Gene score misZ 2.9201 (greater than the threshold 3.09). Trascript score misZ 4.3251 (greater than threshold 3.09). GenCC has associacion of gene with infantile cerebellar-retinal degeneration, autosomal recessive optic atrophy, optic atrophy 9.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.921
• PP5: Variant 22-41526302-G-A is Pathogenic according to our data. Variant chr22-41526302-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 214024.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO2	NM_001098.3	c.1802G>A	p.Gly601Asp	missense_variant	15/18	ENST00000216254.9	NP_001089.1
POLR3H	NM_001018050.4	c.*2981C>T		3_prime_UTR_variant	6/6	ENST00000355209.9	NP_001018060.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACO2	ENST00000216254.9	c.1802G>A	p.Gly601Asp	missense_variant	15/18	1	NM_001098.3	ENSP00000216254	P3
POLR3H	ENST00000355209.9	c.*2981C>T		3_prime_UTR_variant	6/6	1	NM_001018050.4	ENSP00000347345	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 09, 2022	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ACO2 protein function. ClinVar contains an entry for this variant (Variation ID: 214024). This variant has not been reported in the literature in individuals affected with ACO2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 601 of the ACO2 protein (p.Gly601Asp). -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2014	p.Gly601Asp (GGC>GAC): c.1802 G>A in exon 15 of the ACO2 gene (NM_001098.2). The G601D variant that is likely pathogenic was identified in the ACO2 gene. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The G601D variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in OAPEO-MITOP panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;.
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	5.1	H;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-7.0	D;D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.74		.;Loss of sheet (P = 0.0457);
MVP		0.86
MPC		1.9
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.96
gMVP		0.99

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: rs863223881; hg19: chr22-41922306;