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rs730880032

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PM5BP4

The NM_213720.3(CHCHD10):c.43C>T(p.Arg15Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000245 in 1,223,308 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000019 ( 0 hom. )

Consequence

CHCHD10
NM_213720.3 missense, splice_region

Scores

2
8
8
Splicing: ADA: 0.8876
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44
Variant links:
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-23767591-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 180220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP4
Computational evidence support a benign effect (MetaRNN=0.36681676).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CHCHD10NM_213720.3 linkuse as main transcriptc.43C>T p.Arg15Cys missense_variant, splice_region_variant 2/4 ENST00000484558.3
CHCHD10NM_001301339.2 linkuse as main transcriptc.43C>T p.Arg15Cys missense_variant, splice_region_variant 2/4
CHCHD10NR_125755.2 linkuse as main transcriptn.140-52C>T intron_variant, non_coding_transcript_variant
CHCHD10NR_125756.2 linkuse as main transcriptn.139+242C>T intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CHCHD10ENST00000484558.3 linkuse as main transcriptc.43C>T p.Arg15Cys missense_variant, splice_region_variant 2/41 NM_213720.3 P1
CHCHD10ENST00000401675.7 linkuse as main transcriptc.43C>T p.Arg15Cys missense_variant, splice_region_variant 2/45
CHCHD10ENST00000520222.1 linkuse as main transcriptc.41+242C>T intron_variant 3
CHCHD10ENST00000517886.1 linkuse as main transcriptc.42-52C>T intron_variant, NMD_transcript_variant 3

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151972
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000187
AC:
2
AN:
1071336
Hom.:
0
Cov.:
16
AF XY:
0.00000191
AC XY:
1
AN XY:
522302
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000229
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
151972
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74228
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

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 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 02, 2024This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 15 of the CHCHD10 protein (p.Arg15Cys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHCHD10-related conditions. ClinVar contains an entry for this variant (Variation ID: 1897589). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts the p.Arg15 amino acid residue in CHCHD10. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25113787, 25261972, 25681414, 28585542). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.36
BayesDel_addAF
Benign
-0.025
T
BayesDel_noAF
Benign
-0.27
Cadd
Pathogenic
28
Dann
Uncertain
0.99
DEOGEN2
Benign
0.070
T;T
Eigen
Uncertain
0.37
Eigen_PC
Uncertain
0.28
FATHMM_MKL
Benign
0.61
D
LIST_S2
Benign
0.69
T;T
M_CAP
Pathogenic
0.82
D
MetaRNN
Benign
0.37
T;T
MetaSVM
Benign
-0.62
T
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-2.7
D;D
REVEL
Uncertain
0.34
Sift
Uncertain
0.010
D;D
Sift4G
Uncertain
0.0030
D;D
Polyphen
1.0
.;D
Vest4
0.17
MutPred
0.38
Loss of methylation at R15 (P = 0.0089);Loss of methylation at R15 (P = 0.0089);
MVP
0.37
MPC
0.68
ClinPred
0.92
D
GERP RS
4.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
3.1
Varity_R
0.27
gMVP
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.89
dbscSNV1_RF
Benign
0.65
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs730880032; hg19: chr22-24109779; API