rs775332895
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_213720.3(CHCHD10):c.239C>T(p.Pro80Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000264 in 1,608,752 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_213720.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHCHD10 | NM_213720.3 | c.239C>T | p.Pro80Leu | missense_variant | Exon 2 of 4 | ENST00000484558.3 | NP_998885.1 | |
CHCHD10 | NM_001301339.2 | c.239C>T | p.Pro80Leu | missense_variant | Exon 2 of 4 | NP_001288268.1 | ||
CHCHD10 | NR_125755.2 | n.284C>T | non_coding_transcript_exon_variant | Exon 2 of 4 | ||||
CHCHD10 | NR_125756.2 | n.139+438C>T | intron_variant | Intron 1 of 2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHCHD10 | ENST00000484558.3 | c.239C>T | p.Pro80Leu | missense_variant | Exon 2 of 4 | 1 | NM_213720.3 | ENSP00000418428.3 | ||
CHCHD10 | ENST00000401675.7 | c.239C>T | p.Pro80Leu | missense_variant | Exon 2 of 4 | 5 | ENSP00000384973.3 | |||
CHCHD10 | ENST00000520222.1 | c.41+438C>T | intron_variant | Intron 1 of 2 | 3 | ENSP00000430042.1 | ||||
CHCHD10 | ENST00000517886.1 | n.186C>T | non_coding_transcript_exon_variant | Exon 2 of 4 | 3 | ENSP00000429976.1 |
Frequencies
GnomAD3 genomes AF: 0.000250 AC: 38AN: 152144Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.000316 AC: 75AN: 237052Hom.: 0 AF XY: 0.000314 AC XY: 41AN XY: 130380
GnomAD4 exome AF: 0.000265 AC: 386AN: 1456490Hom.: 2 Cov.: 36 AF XY: 0.000283 AC XY: 205AN XY: 724390
GnomAD4 genome AF: 0.000250 AC: 38AN: 152262Hom.: 1 Cov.: 33 AF XY: 0.000282 AC XY: 21AN XY: 74454
ClinVar
Submissions by phenotype
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 Benign:1Other:1
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GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Amyotrophic lateral sclerosis Uncertain:1
This sequence change is predicted to replace proline with leucine at codon 80 of the CHCHD10 protein, p.(Pro80Leu). The proline residue is highly conserved (100 vertebrates, UCSC), and is not located in a known functional domain. There is a moderate physicochemical difference between proline and leucine. The variant is present in a large population cohort at a frequency of 0.03% (rs775332895, 76/268,368 alleles, 0 homozygotes in gnomAD v2.1), with a frequency of 0.3% in the Ashkenazi Jewish population (33/10,032 alleles in gnomAD v2.1). It has been reported as benign, likely benign, a variant of uncertain significance, and pathogenic (ClinVar ID: 204292). The variant has been identified in sporadic and familial amyotrophic lateral sclerosis cases (PMID: 25576308, 30014597, 31690696). It abrogates protein function in the nucleus and mitochondria, reducing respiration and increasing reactive oxygen species in an in vitro functional assay (PMID: 29540477). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms predict deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.3.2, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PS3_Supporting. -
Lower motor neuron syndrome with late-adult onset Benign:1
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Inborn genetic diseases Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
CHCHD10-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
not provided Benign:1
CHCHD10: BP4, BS1 -
Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at