22-23767591-C-T

Position:

• chr22-23767591-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_213720.3(CHCHD10):​c.44G>A​(p.Arg15His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000105 in 949,584 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 predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: CHCHD10 NM_213720.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25826192).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD10	NM_213720.3	c.44G>A	p.Arg15His	missense_variant, splice_region_variant	2/4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2	c.44G>A	p.Arg15His	missense_variant, splice_region_variant	2/4		NP_001288268.1
CHCHD10	NR_125755.2	n.140-51G>A		intron_variant, non_coding_transcript_variant
CHCHD10	NR_125756.2	n.139+243G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3	c.44G>A	p.Arg15His	missense_variant, splice_region_variant	2/4	1	NM_213720.3	ENSP00000418428	P1
CHCHD10	ENST00000401675.7	c.44G>A	p.Arg15His	missense_variant, splice_region_variant	2/4	5		ENSP00000384973
CHCHD10	ENST00000520222.1	c.41+243G>A		intron_variant		3		ENSP00000430042
CHCHD10	ENST00000517886.1	c.42-51G>A		intron_variant, NMD_transcript_variant		3		ENSP00000429976

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000105 AC: 1 AN: 949584 Hom.: 0 Cov.: 15 AF XY: 0.00000215 AC XY: 1 AN XY: 465676

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: 0.00000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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 submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 23, 2019

The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces arginine with histidine at codon 15 of the CHCHD10 protein (p.Arg15His). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and histidine. This variant has not been reported in the literature in individuals with CHCHD10-related conditions. 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. This variant disrupts the p.Arg15 amino acid residue in CHCHD10. Other variant(s) that disrupt this residue (p.Arg15Leu) have been determined to be pathogenic (PMID: 25113787, 25261972, 25681414, 28585542, 29121267, 29315381, 29789341). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.057	T;T
Eigen	Benign	0.018
Eigen_PC	Benign	-0.097
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.5	.;M
MutationTaster	Benign	0.92	D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.26
Sift	Uncertain	0.0030	D;D
Sift4G	Uncertain	0.024	D;D
Polyphen		1.0	.;D
Vest4		0.19
MutPred		0.29		Loss of methylation at R15 (P = 0.0089);Loss of methylation at R15 (P = 0.0089);
MVP		0.36
MPC		0.63
ClinPred		0.79	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.23
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs730880030; hg19: chr22-24109778;