rs542541060

chr22-23767421-C-Gchr22-23767421-C-T

Variant summary

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

The NM_213720.3(CHCHD10):c.214G>C(p.Ala72Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. A72T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHCHD10	NM_213720.3	c.214G>C	p.Ala72Pro	missense_variant	2/4	ENST00000484558.3
CHCHD10	NM_001301339.2	c.214G>C	p.Ala72Pro	missense_variant	2/4
CHCHD10	NR_125755.2	n.259G>C		non_coding_transcript_exon_variant	2/4
CHCHD10	NR_125756.2	n.139+413G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD10	ENST00000484558.3	c.214G>C	p.Ala72Pro	missense_variant	2/4	1	NM_213720.3	P1
CHCHD10	ENST00000401675.7	c.214G>C	p.Ala72Pro	missense_variant	2/4	5
CHCHD10	ENST00000520222.1	c.41+413G>C		intron_variant		3
CHCHD10	ENST00000517886.1	c.161G>C	p.Ser54Thr	missense_variant, NMD_transcript_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Invitae

Sep 18, 2018

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 are either unavailable or 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 alanine with proline at codon 72 of the CHCHD10 protein (p.Ala72Pro). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and proline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Benign	-0.21
Cadd	Pathogenic	32
Dann	Benign	0.96
DEOGEN2	Benign	0.079	T;T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Uncertain	0.45	T;T
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.17
Sift	Benign	0.16	T;T
Sift4G	Benign	0.21	T;T
Polyphen		1.0	.;D
Vest4		0.52
MutPred		0.20		Gain of glycosylation at A72 (P = 0.0333);Gain of glycosylation at A72 (P = 0.0333);
MVP		0.29
MPC		1.6
ClinPred		0.93	D
GERP RS		3.7
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.1
Varity_R		0.62
gMVP		0.73

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: rs542541060; hg19: chr22-24109608;