22-23766263-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_213720.3(CHCHD10):c.274G>A(p.Ala92Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000048 in 791,024 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A92P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., cov: 22)

Exomes 𝑓: 0.000046 ( 0 hom. )

Consequence

CHCHD10
NM_213720.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: -0.886

Publications

4 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: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.028162599).

BP6

Variant 22-23766263-C-T is Benign according to our data. Variant chr22-23766263-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 540611.

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHCHD10	NM_213720.3 link	c.274G>A	p.Ala92Thr	missense_variant	Exon 3 of 4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2 link	c.295G>A	p.Ala99Thr	missense_variant	Exon 3 of 4		NP_001288268.1
CHCHD10	NR_125755.2 link	n.319G>A		non_coding_transcript_exon_variant	Exon 3 of 4
CHCHD10	NR_125756.2 link	n.152G>A		non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3 link	c.274G>A	p.Ala92Thr	missense_variant	Exon 3 of 4	1	NM_213720.3	ENSP00000418428.3

Frequencies

GnomAD3 genomes

AF:

0.0000627

AC:

AN:

79792

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000139

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000742

AC:

AN:

80812

AF XY:

0.0000665

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000964

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000162

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000464

AC:

AN:

711232

Hom.:

Cov.:

AF XY:

0.0000534

AC XY:

AN XY:

356026

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

18382

American (AMR)

AF:

0.0000938

AC:

AN:

21328

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14952

East Asian (EAS)

AF:

0.00

AC:

AN:

21834

South Asian (SAS)

AF:

0.00

AC:

AN:

43822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2166

European-Non Finnish (NFE)

AF:

0.0000567

AC:

AN:

529292

Other (OTH)

AF:

0.0000328

AC:

AN:

30472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.551

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

AF:

0.0000627

AC:

AN:

79792

Hom.:

Cov.:

AF XY:

0.0000522

AC XY:

AN XY:

38338

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24162

American (AMR)

AF:

0.00

AC:

AN:

7166

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

1944

East Asian (EAS)

AF:

0.00

AC:

AN:

2850

South Asian (SAS)

AF:

0.00

AC:

AN:

2134

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

194

European-Non Finnish (NFE)

AF:

0.000139

AC:

AN:

36088

Other (OTH)

AF:

0.00

AC:

AN:

1032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000126

AC:

ExAC

AF:

0.0000311

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

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

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 92 of the CHCHD10 protein (p.Ala92Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with amyotrophic lateral sclerosis (ALS) (PMID: 25726362). ClinVar contains an entry for this variant (Variation ID: 540611). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Inborn genetic diseases

Benign:1

Dec 06, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.90

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.019

T;T

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.076

LIST_S2

Benign

0.28

T;T

M_CAP

Benign

0.0066

MetaRNN

Benign

0.028

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;N

PhyloP100

-0.89

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.71

N;N

REVEL

Benign

0.013

Sift

Benign

0.74

T;T

Sift4G

Benign

0.26

T;T

Vest4

0.086

ClinPred

0.020

GERP RS

-6.6

Varity_R

0.035

gMVP

0.36

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over