chr22-41526316-T-TTCCGTGGGCACTTGGATAACATCTCCAACAACCTGCTCATTGGTGCCATCAACATTGAAAACGGCAAGGCCAAC

Position:

• chr22-41526316-T-TTCCGTGGGCACTTGGATAACATCTCCAACAACCTGCTCATTGGTGCCATCAACATTGAAAACGGCAAGGCCAAC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001098.3(ACO2):​c.1823_1896dup​(p.Arg633GlyfsTer52) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ACO2 NM_001098.3 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.67

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-41526316-T-TTCCGTGGGCACTTGGATAACATCTCCAACAACCTGCTCATTGGTGCCATCAACATTGAAAACGGCAAGGCCAAC is Pathogenic according to our data. Variant chr22-41526316-T-TTCCGTGGGCACTTGGATAACATCTCCAACAACCTGCTCATTGGTGCCATCAACATTGAAAACGGCAAGGCCAAC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1709577.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACO2	NM_001098.3	c.1823_1896dup	p.Arg633GlyfsTer52	frameshift_variant	15/18	ENST00000216254.9	NP_001089.1
POLR3H	NM_001018050.4	c.*2966_*2967insGTTGGCCTTGCCGTTTTCAATGTTGATGGCACCAATGAGCAGGTTGTTGGAGATGTTATCCAAGTGCCCACGGA		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.1823_1896dup	p.Arg633GlyfsTer52	frameshift_variant	15/18	1	NM_001098.3	ENSP00000216254	P3
POLR3H	ENST00000355209.9	c.*2966_*2967insGTTGGCCTTGCCGTTTTCAATGTTGATGGCACCAATGAGCAGGTTGTTGGAGATGTTATCCAAGTGCCCACGGA		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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Optic atrophy 9 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

Jun 23, 2022

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-41922320;