22-41527949-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP2PP3

The NM_001098.3(ACO2):ā€‹c.2135C>Gā€‹(p.Pro712Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P712L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

ACO2
NM_001098.3 missense

Scores

7
10
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.18
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-41527949-C-T is described in Lovd as [Likely_pathogenic].
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, 0.805

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ACO2NM_001098.3 linkuse as main transcriptc.2135C>G p.Pro712Arg missense_variant 17/18 ENST00000216254.9 NP_001089.1 Q99798
POLR3HNM_001018050.4 linkuse as main transcriptc.*1334G>C 3_prime_UTR_variant 6/6 ENST00000355209.9 NP_001018060.1 Q9Y535-1A0A024R1P3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ACO2ENST00000216254.9 linkuse as main transcriptc.2135C>G p.Pro712Arg missense_variant 17/181 NM_001098.3 ENSP00000216254.4 Q99798
POLR3HENST00000355209.9 linkuse as main transcriptc.*1334G>C 3_prime_UTR_variant 6/61 NM_001018050.4 ENSP00000347345.4 Q9Y535-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250696
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135520
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461884
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Uncertain
0.061
T
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.79
D;.
Eigen
Pathogenic
0.70
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Uncertain
0.14
D
MetaRNN
Pathogenic
0.81
D;D
MetaSVM
Uncertain
-0.22
T
MutationAssessor
Pathogenic
3.6
H;.
PrimateAI
Pathogenic
0.82
D
PROVEAN
Pathogenic
-7.8
D;D
REVEL
Uncertain
0.36
Sift
Uncertain
0.0020
D;D
Sift4G
Uncertain
0.059
T;T
Polyphen
1.0
D;P
Vest4
0.87
MutPred
0.53
.;Gain of catalytic residue at P737 (P = 0.0409);
MVP
0.79
MPC
1.7
ClinPred
1.0
D
GERP RS
3.9
Varity_R
0.92
gMVP
0.85

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs375761361; hg19: chr22-41923953; API