rs931085449

Positions:

• chr22-23766188-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_213720.3(CHCHD10):​c.349A>T​(p.Ser117Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,438 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 (★★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.624

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3296717).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD10	NM_213720.3	c.349A>T	p.Ser117Cys	missense_variant	3/4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2	c.370A>T	p.Ser124Cys	missense_variant	3/4		NP_001288268.1
CHCHD10	NR_125755.2	n.394A>T		non_coding_transcript_exon_variant	3/4
CHCHD10	NR_125756.2	n.227A>T		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3	c.349A>T	p.Ser117Cys	missense_variant	3/4	1	NM_213720.3	ENSP00000418428.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460438 Hom.: 0 Cov.: 65 AF XY: 0.00000275 AC XY: 2 AN XY: 726418

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Oct 20, 2021

_x000D_ Criteria applied: PS4_SUP, PM2_SUP, PP3 -

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

Labcorp Genetics (formerly Invitae), Labcorp

Sep 24, 2019

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 C15"). 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 serine with cysteine at codon 117 of the CHCHD10 protein (p.Ser117Cys). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Benign	0.92
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.45	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.33	T
MetaSVM	Uncertain	0.21	D
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.13
Vest4		0.34
MutPred		0.26		Loss of MoRF binding (P = 0.0028);
MVP		0.19
ClinPred		0.96	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs931085449; hg19: chr22-24108375;