1-244842061-G-C
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_198076.6(COX20):c.157+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000876 in 1,587,306 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.00063 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00090 ( 0 hom. )
Consequence
COX20
NM_198076.6 splice_region, intron
NM_198076.6 splice_region, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.62
Genes affected
COX20 (HGNC:26970): (cytochrome c oxidase assembly factor COX20) This gene encodes a protein that plays a role in the assembly of cytochrome C oxidase, an important component of the respiratory pathway. It contains two transmembrane helices and localizes to the mitochondrial membrane. Mutations in this gene can cause mitochondrial complex IV deficiency, which results in ataxia and muscle hypotonia. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]
HNRNPU (HGNC:5048): (heterogeneous nuclear ribonucleoprotein U) This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14. [provided by RefSeq, Jun 2017]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-244842061-G-C is Pathogenic according to our data. Variant chr1-244842061-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 380082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000632 AC: 96AN: 151860Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
96
AN:
151860
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000568 AC: 142AN: 249980Hom.: 0 AF XY: 0.000606 AC XY: 82AN XY: 135228
GnomAD3 exomes
AF:
AC:
142
AN:
249980
Hom.:
AF XY:
AC XY:
82
AN XY:
135228
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000902 AC: 1295AN: 1435446Hom.: 0 Cov.: 25 AF XY: 0.000854 AC XY: 611AN XY: 715794
GnomAD4 exome
AF:
AC:
1295
AN:
1435446
Hom.:
Cov.:
25
AF XY:
AC XY:
611
AN XY:
715794
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.000632 AC: 96AN: 151860Hom.: 0 Cov.: 32 AF XY: 0.000634 AC XY: 47AN XY: 74134
GnomAD4 genome
AF:
AC:
96
AN:
151860
Hom.:
Cov.:
32
AF XY:
AC XY:
47
AN XY:
74134
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Mitochondrial complex 4 deficiency, nuclear type 11 Pathogenic:6
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 17, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Dec 18, 2020 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 04, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jun 30, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Oct 09, 2024 | Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex IV deficiency, nuclear type 11 (MIM#619054). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity (OMIM). (I) 0209 - Splice site variant proven to affect splicing of the transcript with uncertain effect on protein sequence. This variant is predicted to result in an out-of- frame loss of exon 2. RT-PCR experiments using patient cells demonstrates an increased expression of the exon 2 deletion transcript and loss of the full length WT transcript compared with control cells (PMID: 30656193). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v4) <0.01 for a recessive condition (1391 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2; 1 heterozygote, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical diagnostic laboratories and has been reported in multiple affected compound heterozygous individuals (ClinVar, PMIDs: 30656193). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 09, 2023 | Variant summary: COX20 c.157+3G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a canonical 5' splicing donor site. This impact on normal splicing was confirmed experimentally using fibroblasts from a compound heterozygous patient: only mRNA transcripts missing exon 2 could be detected, and full length COX20 mRNA transcripts were completely absent (Otero_2019). Furthermore, no protein products could be detected from these same patient fibroblasts, indicating a complete loss of protein product (Otero_2019). The variant allele was found at a frequency of 0.00057 in 249980 control chromosomes (gnomAD). c.157+3G>C has been reported in the literature as a biallelic genotype in multiple individuals affected with Mitochondrial Complex 4 Deficiency, Nuclear Type 11 (e.g. Otero_2019, Chakravorty_2020, Naess_2021). These data indicate that the variant is very likely to be associated with disease.The following publications have been ascertained in the context of this evaluation (PMID: 32999401, 32827528, 30656193). Seven ClinVar submitters have assessed the variant since 2014: one classified the variant as uncertain significance, four as likely pathogenic, and two as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:3Uncertain:2
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 24, 2025 | Published mRNA and protein analysis in fibroblasts from an individual with this variant demonstrated an absence of full-length mRNA and COX20 protein (PMID: 30656193); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 32999401, 32606554, 32827528, 30656193, 37095481) - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 15, 2025 | This sequence change falls in intron 2 of the COX20 gene. It does not directly change the encoded amino acid sequence of the COX20 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs367956888, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individuals with clinical features of mitochondrial complex IV deficiency (PMID: 30656193, 32827528, 32999401). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 380082). Studies have shown that this variant alters COX20 gene expression (PMID: 30656193). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 16, 2023 | PP1_strong, PP3, PM3_very_strong, PS3 - |
Mitochondrial complex IV deficiency, nuclear type 1 Uncertain:1
| Uncertain significance, flagged submission | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at