rs587777574

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_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

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 7.64

Publications

69 publications found

Variant links:

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

CHCHD10 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 140745.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD10	NM_213720.3 link	c.176C>T	p.Ser59Leu	missense_variant	Exon 2 of 4	ENST00000484558.3	NP_998885.1	Q8WYQ3
CHCHD10	NM_001301339.2 link	c.176C>T	p.Ser59Leu	missense_variant	Exon 2 of 4		NP_001288268.1	Q8WYQ3B5MBW9
CHCHD10	NR_125755.2 link	n.221C>T		non_coding_transcript_exon_variant	Exon 2 of 4
CHCHD10	NR_125756.2 link	n.139+375C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHCHD10	ENST00000484558.3 link	c.176C>T	p.Ser59Leu	missense_variant	Exon 2 of 4	1	NM_213720.3	ENSP00000418428.3	Q8WYQ3
CHCHD10	ENST00000401675.7 link	c.176C>T	p.Ser59Leu	missense_variant	Exon 2 of 4	5		ENSP00000384973.3	B5MBW9
CHCHD10	ENST00000517886.1 link	n.123C>T		non_coding_transcript_exon_variant	Exon 2 of 4	3		ENSP00000429976.1	E5RGN4
CHCHD10	ENST00000520222.1 link	c.41+375C>T		intron_variant	Intron 1 of 2	3		ENSP00000430042.1	E5RH03

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.91e-7

AC:

AN:

1446818

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

719022

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32774

American (AMR)

AF:

0.00

AC:

AN:

43614

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25774

East Asian (EAS)

AF:

0.00

AC:

AN:

38824

South Asian (SAS)

AF:

0.00

AC:

AN:

84428

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50970

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4270

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1106508

Other (OTH)

AF:

0.00

AC:

AN:

59656

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Frontotemporal dementia and/or amyotrophic lateral sclerosis 2

Pathogenic:3

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2_Supporting+PS3+PP1_Strong+PS4_Supporting -

Aug 01, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 31, 2020

Suna and Inan Kirac Foundation Neurodegeneration Research Laboratory, Koc University

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:2

Nov 23, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant mitochondrial myopathy with exercise intolerance

Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

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

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.50

D;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

D;D

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Benign

-0.30

MutationAssessor

Pathogenic

3.8

.;H

PhyloP100

7.6

PrimateAI

Pathogenic

0.84

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

GERP RS

3.7

PromoterAI

-0.034

Neutral

(source)

Varity_R

0.74

gMVP

0.80

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over