rs730880030

Positions:

• chr22-23767591-C-A
• chr22-23767591-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_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 (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHCHD10 NM_213720.3 missense, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 U:1 O: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 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	UniProt
CHCHD10	NM_213720.3	c.44G>T	p.Arg15Leu	missense_variant, splice_region_variant	2/4	ENST00000484558.3
CHCHD10	NM_001301339.2	c.44G>T	p.Arg15Leu	missense_variant, splice_region_variant	2/4
CHCHD10	NR_125755.2	n.140-51G>T		intron_variant, non_coding_transcript_variant
CHCHD10	NR_125756.2	n.139+243G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD10	ENST00000484558.3	c.44G>T	p.Arg15Leu	missense_variant, splice_region_variant	2/4	1	NM_213720.3	P1
CHCHD10	ENST00000401675.7	c.44G>T	p.Arg15Leu	missense_variant, splice_region_variant	2/4	5
CHCHD10	ENST00000520222.1	c.41+243G>T		intron_variant		3
CHCHD10	ENST00000517886.1	c.42-51G>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 949590 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 465678

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Uncertain:1 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, no assertion criteria provided	literature only	OMIM	Jan 01, 2015	- -
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) -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.029	T;T
Eigen	Benign	0.051
Eigen_PC	Benign	-0.085
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.8	.;M
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.013	D;D
Sift4G	Uncertain	0.019	D;D
Polyphen		0.99	.;D
Vest4		0.74
MutPred		0.32		Loss of methylation at R15 (P = 0.0089);Loss of methylation at R15 (P = 0.0089);
MVP		0.33
MPC		0.63
ClinPred		0.81	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.2
Varity_R		0.33
gMVP		0.39

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;