chr22-23767591-C-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_213720.3(CHCHD10):c.44G>T(p.Arg15Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
CHCHD10
NM_213720.3 missense, splice_region
NM_213720.3 missense, splice_region
Scores
3
5
11
Clinical Significance
Conservation
PhyloP100: 0.295
Genes affected
CHCHD10 (HGNC:15559): (coiled-coil-helix-coiled-coil-helix domain containing 10) This gene encodes a mitochondrial protein that is enriched at cristae junctions in the intermembrane space. It may play a role in cristae morphology maintenance or oxidative phosphorylation. Mutations in this gene cause frontotemporal dementia and/or amyotrophic lateral sclerosis-2. Alternative splicing of this gene results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 7 and 19. [provided by RefSeq, Aug 2014]
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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 22-23767591-C-A is Pathogenic according to our data. Variant chr22-23767591-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHCHD10 | NM_213720.3 | c.44G>T | p.Arg15Leu | missense_variant, splice_region_variant | 2/4 | ENST00000484558.3 | NP_998885.1 | |
CHCHD10 | NM_001301339.2 | c.44G>T | p.Arg15Leu | missense_variant, splice_region_variant | 2/4 | NP_001288268.1 | ||
CHCHD10 | NR_125755.2 | n.140-51G>T | intron_variant | |||||
CHCHD10 | NR_125756.2 | n.139+243G>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHCHD10 | ENST00000484558.3 | c.44G>T | p.Arg15Leu | missense_variant, splice_region_variant | 2/4 | 1 | NM_213720.3 | ENSP00000418428.3 | ||
CHCHD10 | ENST00000401675.7 | c.44G>T | p.Arg15Leu | missense_variant, splice_region_variant | 2/4 | 5 | ENSP00000384973.3 | |||
CHCHD10 | ENST00000520222.1 | c.41+243G>T | intron_variant | 3 | ENSP00000430042.1 | |||||
CHCHD10 | ENST00000517886.1 | n.42-51G>T | intron_variant | 3 | ENSP00000429976.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 949590Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0AN XY: 465678
GnomAD4 exome
Data not reliable, filtered out with message: AC0;AS_VQSR
AF:
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0
AN:
949590
Hom.:
Cov.:
15
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0
AN XY:
465678
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3Uncertain:1Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 04, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29789341, 29121267, 29315381, 33772006, 36158221, 35323676, 36625206, 33659869, 34899176, 35787294, 36799027, 34965490, 35032474, 35709007, 35362877, 26152333, 25348631, 25576308, 25193783, 25681414, 25833818, 38132101, 37686461, 37021679, 38002924, 37566027, 28585542, 35700042, 26131548, 30014597, 25261972, 32042922, 25113787) - |
Uncertain significance, no assertion criteria provided | literature only | OMIM | Jan 01, 2015 | - - |
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Sep 14, 2022 | ACMG criteria used to clasify this variant: PS3, PM2, PS4, PP1 - |
Lower motor neuron syndrome with late-adult onset;C4014648:Frontotemporal dementia and/or amyotrophic lateral sclerosis 2;C4015513:Autosomal dominant mitochondrial myopathy with exercise intolerance Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 25, 2023 | This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 15 of the CHCHD10 protein (p.Arg15Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (PMID: 25113787, 25261972, 25681414, 25833818, 26152333, 30014597). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180220). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects CHCHD10 function (PMID: 28585542, 29112723, 29121267, 29315381, 29789341). For these reasons, this variant has been classified as Pathogenic. - |
Autosomal dominant mitochondrial myopathy with exercise intolerance Other:1
not provided, no classification provided | literature only | GeneReviews | - | Variant observed to segregate with ALS (amyotrophic lateral sclerosis), in several families; likely responsible for less than 1 percent of familial ALS. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;M
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
0.99
.;D
Vest4
MutPred
Loss of methylation at R15 (P = 0.0089);Loss of methylation at R15 (P = 0.0089);
MVP
MPC
0.63
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at