rs786204829

Variant names:

• chr22-41528022-G-C
• rs786204829
• NM_001098.3:c.2208G>C

Your query was ambiguous. Multiple possible variants found:

• chr22-41528022-G-C
• chr22-41528022-G-A
• chr22-41528022-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_001098.3(ACO2):​c.2208G>C​(p.Lys736Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACO2 NM_001098.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.91
• Publications: 10 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]

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]

POLR3H Gene-Disease associations (from GenCC):

• 46 XX gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a modified_residue N6-acetyllysine (size 0) in uniprot entity ACON_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant 22-41528022-G-C is Pathogenic according to our data. Variant chr22-41528022-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 189313.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	NM_001098.3	MANE Select	c.2208G>C	p.Lys736Asn	missense splice_region	Exon 17 of 18	NP_001089.1	Q99798
	POLR3H	NM_001018050.4	MANE Select	c.*1261C>G		3_prime_UTR	Exon 6 of 6	NP_001018060.1	Q9Y535-1
	POLR3H	NM_001282884.2		c.*1261C>G		3_prime_UTR	Exon 7 of 7	NP_001269813.1	Q9Y535-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACO2	ENST00000216254.9	TSL:1 MANE Select	c.2208G>C	p.Lys736Asn	missense splice_region	Exon 17 of 18	ENSP00000216254.4	Q99798
	POLR3H	ENST00000355209.9	TSL:1 MANE Select	c.*1261C>G		3_prime_UTR	Exon 6 of 6	ENSP00000347345.4	Q9Y535-1
	ACO2	ENST00000878390.1		c.2424G>C	p.Lys808Asn	missense splice_region	Exon 19 of 20	ENSP00000548449.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Infantile cerebellar-retinal degeneration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	35
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.9
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.041	D
Polyphen		0.021	B
Vest4		0.63
MutPred		0.39		Loss of glycosylation at K761 (P = 0.0569)
MVP		0.65
MPC		1.1
ClinPred		0.98	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.64
gMVP		0.83
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs786204829; hg19: chr22-41924026;