rs141772938

Variant names:

• chr22-41507837-C-G
• rs141772938
• NM_001098.3:c.220C>G

Your query was ambiguous. Multiple possible variants found:

• chr22-41507837-C-G
• chr22-41507837-C-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001098.3(ACO2):​c.220C>G​(p.Leu74Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,614,196 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0036 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (26 hom.)
• Consequence: ACO2 NM_001098.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:8 B:4 O:1
• Conservation: PhyloP100: 0.864
• Publications: 25 publications found

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]

ACO2 Gene-Disease associations (from GenCC):

• infantile cerebellar-retinal degeneration

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)
• optic atrophy 9

  Inheritance: Unknown, AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• autosomal recessive optic atrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018066943).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00362 (552/152372) while in subpopulation NFE AF = 0.0062 (422/68044). AF 95% confidence interval is 0.00571. There are 1 homozygotes in GnomAd4. There are 262 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 26 Unknown,AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	NM_001098.3	MANE Select	c.220C>G	p.Leu74Val	missense	Exon 3 of 18	NP_001089.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	ENST00000216254.9	TSL:1 MANE Select	c.220C>G	p.Leu74Val	missense	Exon 3 of 18	ENSP00000216254.4
	ACO2	ENST00000396512.3	TSL:5	c.220C>G	p.Leu74Val	missense	Exon 3 of 18	ENSP00000379769.3
	ACO2	ENST00000678269.1		c.220C>G	p.Leu74Val	missense	Exon 3 of 18	ENSP00000504150.1

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 553 AN: 152254 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00273

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00370 AC: 929 AN: 250844 AF XY: 0.00377

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00324

Gnomad NFE exome AF: 0.00648

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00471 AC: 6886 AN: 1461824 Hom.: 26 Cov.: 33 AF XY: 0.00456 AC XY: 3317 AN XY: 727214

African (AFR) AF: 0.000747 AC: 25 AN: 33478

American (AMR) AF: 0.000895 AC: 40 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00182 AC: 157 AN: 86244

European-Finnish (FIN) AF: 0.00369 AC: 197 AN: 53416

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00563 AC: 6256 AN: 1111984

Other (OTH) AF: 0.00341 AC: 206 AN: 60392

GnomAD4 genome AF: 0.00362 AC: 552 AN: 152372 Hom.: 1 Cov.: 32 AF XY: 0.00352 AC XY: 262 AN XY: 74518

African (AFR) AF: 0.000938 AC: 39 AN: 41588

American (AMR) AF: 0.00372 AC: 57 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00273 AC: 29 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00620 AC: 422 AN: 68044

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00462 Hom.: 1

Bravo AF: 0.00354

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00547 AC: 47

ExAC AF: 0.00410 AC: 498

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00458

EpiControl AF: 0.00498

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
2	3	2	not provided (7)
-	1	-	ACO2-related disorder (1)
-	-	1	Infantile cerebellar-retinal degeneration (1)
-	1	-	Infantile cerebellar-retinal degeneration;C4225384:Optic atrophy 9 (2)
-	-	1	not specified (1)
-	1	-	Optic atrophy (1)
-	1	-	Optic atrophy 9 (1)
1	-	-	OPTIC ATROPHY 9, AUTOSOMAL RECESSIVE (1)
-	1	-	Retinal dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.32
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		0.86
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.010	D
Polyphen		0.55	P
Vest4		0.74
MVP		0.50
MPC		0.86
ClinPred		0.11	T
GERP RS		2.5
Varity_R		0.52
gMVP		0.65
Mutation Taster		=66/34	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs141772938; hg19: chr22-41903841;