22-23767445-C-T

Variant names:

• chr22-23767445-C-T
• rs781304084
• NM_213720.3:c.190G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_213720.3(CHCHD10):​c.190G>A​(p.Val64Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V64V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.15
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_213720.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2094267).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213720.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	NM_213720.3	MANE Select	c.190G>A	p.Val64Ile	missense	Exon 2 of 4	NP_998885.1
	CHCHD10	NM_001301339.2		c.190G>A	p.Val64Ile	missense	Exon 2 of 4	NP_001288268.1
	CHCHD10	NR_125755.2		n.235G>A		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	ENST00000484558.3	TSL:1 MANE Select	c.190G>A	p.Val64Ile	missense	Exon 2 of 4	ENSP00000418428.3
	CHCHD10	ENST00000401675.7	TSL:5	c.190G>A	p.Val64Ile	missense	Exon 2 of 4	ENSP00000384973.3
	CHCHD10	ENST00000517886.1	TSL:3	n.137G>A		non_coding_transcript_exon	Exon 2 of 4	ENSP00000429976.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1451944 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 721788

African (AFR) AF: 0.00 AC: 0 AN: 33172

American (AMR) AF: 0.00 AC: 0 AN: 44136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.00 AC: 0 AN: 84830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4266

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109184

Other (OTH) AF: 0.00 AC: 0 AN: 59822

GnomAD4 genome Cov.: 33

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

Feb 24, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CHCHD10-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with isoleucine at codon 64 of the CHCHD10 protein (p.Val64Ile). The valine residue is moderately conserved and there is a small physicochemical difference between valine and isoleucine.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.060
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.83	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.1
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.11
Sift	Benign	0.066	T
Sift4G	Uncertain	0.055	T
Polyphen		1.0	D
Vest4		0.34
MutPred		0.31		Gain of helix (P = 0.062)
MVP		0.067
MPC		1.3
ClinPred		0.89	D
GERP RS		2.6
PromoterAI		-0.12	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.096
gMVP		0.43
Mutation Taster		=79/21	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: rs781304084; hg19: chr22-24109632;