chr11-85628683-CCCAAG-C
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_018480.7(TMEM126B):c.77_81del(p.Pro26ArgfsTer35) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000000723 in 1,383,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 7.2e-7 ( 0 hom. )
Consequence
TMEM126B
NM_018480.7 frameshift, splice_region
NM_018480.7 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.72
Genes affected
TMEM126B (HGNC:30883): (transmembrane protein 126B) This gene encodes a mitochondrial transmembrane protein which is a component of the mitochondrial complex I assembly complex. The encoded protein serves as an assembly factor that is required for formation of the membrane arm of the complex. It interacts with NADH dehydrogenase [ubiquinone] 1 alpha subcomplex assembly factor 13. Naturally occurring mutations in this gene are associated with isolated complex I deficiency. A pseudogene of this gene has been defined on chromosome 9. [provided by RefSeq, Apr 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 7 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 11-85628683-CCCAAG-C is Pathogenic according to our data. Variant chr11-85628683-CCCAAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 2072804.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TMEM126B | NM_018480.7 | c.77_81del | p.Pro26ArgfsTer35 | frameshift_variant, splice_region_variant | 1/5 | ENST00000358867.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TMEM126B | ENST00000358867.11 | c.77_81del | p.Pro26ArgfsTer35 | frameshift_variant, splice_region_variant | 1/5 | 2 | NM_018480.7 | P1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000719 AC: 1AN: 139118Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 75428
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GnomAD4 exome AF: 7.23e-7 AC: 1AN: 1383828Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 682862
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 08, 2022 | For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with TMEM126B-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Pro26Argfs*35) in the TMEM126B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TMEM126B are known to be pathogenic (PMID: 27374774). - |
Computational scores
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Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at