22-23767844-G-C

Variant names:

• chr22-23767844-G-C
• rs951686050
• NM_213720.3:c.31C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_213720.3(CHCHD10):​c.31C>G​(p.Arg11Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,369,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 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. R11W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.436
• Publications: 1 publications found

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]

CHCHD10 Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant mitochondrial myopathy with exercise intolerance

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• frontotemporal dementia and/or amyotrophic lateral sclerosis 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• lower motor neuron syndrome with late-adult onset

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• frontotemporal dementia with motor neuron disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 uncertain in NM_213720.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.21329212).
• BS2: High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD10	NM_213720.3	c.31C>G	p.Arg11Gly	missense_variant	Exon 1 of 4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2	c.31C>G	p.Arg11Gly	missense_variant	Exon 1 of 4		NP_001288268.1
CHCHD10	NR_125755.2	n.129C>G		non_coding_transcript_exon_variant	Exon 1 of 4
CHCHD10	NR_125756.2	n.129C>G		non_coding_transcript_exon_variant	Exon 1 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3	c.31C>G	p.Arg11Gly	missense_variant	Exon 1 of 4	1	NM_213720.3	ENSP00000418428.3
CHCHD10	ENST00000401675.7	c.31C>G	p.Arg11Gly	missense_variant	Exon 1 of 4	5		ENSP00000384973.3
CHCHD10	ENST00000520222.1	c.31C>G	p.Arg11Gly	missense_variant	Exon 1 of 3	3		ENSP00000430042.1
CHCHD10	ENST00000517886.1	n.31C>G		non_coding_transcript_exon_variant	Exon 1 of 4	3		ENSP00000429976.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000175 AC: 24 AN: 1369552 Hom.: 0 Cov.: 30 AF XY: 0.0000207 AC XY: 14 AN XY: 677532

African (AFR) AF: 0.00 AC: 0 AN: 27708

American (AMR) AF: 0.00 AC: 0 AN: 31694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23036

East Asian (EAS) AF: 0.00 AC: 0 AN: 32246

South Asian (SAS) AF: 0.00 AC: 0 AN: 76524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5416

European-Non Finnish (NFE) AF: 0.0000225 AC: 24 AN: 1067402

Other (OTH) AF: 0.00 AC: 0 AN: 55930

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Jul 06, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BP4, PM2_moderate -

Jun 16, 2022

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 11 of the CHCHD10 protein (p.Arg11Gly). 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: 30014597). ClinVar contains an entry for this variant (Variation ID: 570385). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	Benign	0.15
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.90
DEOGEN2	Benign	0.024	.;T;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.46	T;T;T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	.;.;M
PhyloP100		0.44
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.0	D;N;N
REVEL	Benign	0.13
Sift	Uncertain	0.016	.;D;D
Sift4G	Benign	0.11	.;T;T
Polyphen		0.81	.;.;P
Vest4		0.29
MutPred		0.37		Loss of methylation at R11 (P = 0.0143);Loss of methylation at R11 (P = 0.0143);Loss of methylation at R11 (P = 0.0143);
MVP		0.29
MPC		0.65
ClinPred		0.86	D
GERP RS		2.2
PromoterAI		0.033	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.2
Varity_R		0.13
gMVP		0.43
Mutation Taster		=69/31	polymorphism

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

Other links and lift over

dbSNP: rs951686050; hg19: chr22-24110031;