rs587777574

Positions:

• chr22-23767459-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_213720.3(CHCHD10):​c.176C>T​(p.Ser59Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.64

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 Pathogenic. Variant got 14 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, 8 uncertain in NM_213720.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.912
• PP5: Variant 22-23767459-G-A is Pathogenic according to our data. Variant chr22-23767459-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 140745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23767459-G-A is described in UniProt as null.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHCHD10	NM_213720.3	c.176C>T	p.Ser59Leu	missense_variant	2/4	ENST00000484558.3
CHCHD10	NM_001301339.2	c.176C>T	p.Ser59Leu	missense_variant	2/4
CHCHD10	NR_125755.2	n.221C>T		non_coding_transcript_exon_variant	2/4
CHCHD10	NR_125756.2	n.139+375C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD10	ENST00000484558.3	c.176C>T	p.Ser59Leu	missense_variant	2/4	1	NM_213720.3	P1
CHCHD10	ENST00000401675.7	c.176C>T	p.Ser59Leu	missense_variant	2/4	5
CHCHD10	ENST00000520222.1	c.41+375C>T		intron_variant		3
CHCHD10	ENST00000517886.1	c.123C>T	p.Leu41=	synonymous_variant, NMD_transcript_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.91e-7 AC: 1 AN: 1446818 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 719022

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: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 Pathogenic:2

Likely pathogenic, criteria provided, single submitter	research	Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University	Mar 31, 2020	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2014	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 23, 2022	Published functional studies demonstrate a damaging effect (Bannwarth et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30877432, 28585542, 26666268, 29789341, 24934289, 28749476) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Autosomal dominant mitochondrial myopathy with exercise intolerance Other:1

not provided, no classification provided

literature only

GeneReviews

-

Variant associated with late-onset complex phenotype including motor neuron disease, cognitive decline resembling FTD (frontotemporal dementia), cerebellar ataxia, and myopathy. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.91	D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	3.8	.;H
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.98	.;D
Vest4		0.95
MutPred		0.46		Loss of glycosylation at S59 (P = 0.0017);Loss of glycosylation at S59 (P = 0.0017);
MVP		0.38
MPC		1.0
ClinPred		1.0	D
GERP RS		3.7
Varity_R		0.74
gMVP		0.80

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: rs587777574; hg19: chr22-24109646;