22-23767445-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. 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 (★).

• 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

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=0.2094267).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD10	NM_213720.3	c.190G>A	p.Val64Ile	missense_variant	Exon 2 of 4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2	c.190G>A	p.Val64Ile	missense_variant	Exon 2 of 4		NP_001288268.1
CHCHD10	NR_125755.2	n.235G>A		non_coding_transcript_exon_variant	Exon 2 of 4
CHCHD10	NR_125756.2	n.139+389G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3	c.190G>A	p.Val64Ile	missense_variant	Exon 2 of 4	1	NM_213720.3	ENSP00000418428.3
CHCHD10	ENST00000401675.7	c.190G>A	p.Val64Ile	missense_variant	Exon 2 of 4	5		ENSP00000384973.3
CHCHD10	ENST00000520222.1	c.41+389G>A		intron_variant	Intron 1 of 2	3		ENSP00000430042.1
CHCHD10	ENST00000517886.1	n.137G>A		non_coding_transcript_exon_variant	Exon 2 of 4	3		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

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.: 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 v4.3

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;T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.060
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Uncertain	2.4	.;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.87	N;N
REVEL	Benign	0.11
Sift	Benign	0.066	T;T
Sift4G	Uncertain	0.055	T;T
Polyphen		1.0	.;D
Vest4		0.34
MutPred		0.31		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.067
MPC		1.3
ClinPred		0.89	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.096
gMVP		0.43

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: rs781304084; hg19: chr22-24109632;