22-23766263-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBP6_Very_Strong

The NM_213720.3(CHCHD10):c.274G>C(p.Ala92Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A92T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0015 ( 0 hom., cov: 22)

Exomes 𝑓: 0.098 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CHCHD10
NM_213720.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

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 -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025873482).

BP6

Variant 22-23766263-C-G is Benign according to our data. Variant chr22-23766263-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1259100.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.274G>C	p.Ala92Pro	missense_variant	Exon 3 of 4	ENST00000484558.3	NP_998885.1	Q8WYQ3
CHCHD10	NM_001301339.2 link	c.295G>C	p.Ala99Pro	missense_variant	Exon 3 of 4		NP_001288268.1	Q8WYQ3B5MBW9
CHCHD10	NR_125755.2 link	n.319G>C		non_coding_transcript_exon_variant	Exon 3 of 4
CHCHD10	NR_125756.2 link	n.152G>C		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>C	p.Ala92Pro	missense_variant	Exon 3 of 4	1	NM_213720.3	ENSP00000418428.3		Q8WYQ3

Frequencies

GnomAD3 genomes

AF:

0.00147

AC:

116

AN:

79090

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000749

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00211

Gnomad ASJ

AF:

0.00154

Gnomad EAS

AF:

0.00249

Gnomad SAS

AF:

0.00192

Gnomad FIN

AF:

0.00352

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00151

Gnomad OTH

AF:

0.00195

GnomAD2 exomes

AF:

0.0831

AC:

6718

AN:

80812

AF XY:

0.0786

show subpopulations

Gnomad AFR exome

AF:

0.0284

Gnomad AMR exome

AF:

0.179

Gnomad ASJ exome

AF:

0.0902

Gnomad EAS exome

AF:

0.118

Gnomad FIN exome

AF:

0.0413

Gnomad NFE exome

AF:

0.0649

Gnomad OTH exome

AF:

0.111

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0980

AC:

63389

AN:

646636

Hom.:

Cov.:

AF XY:

0.0985

AC XY:

31896

AN XY:

323752

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0668

AC:

1137

AN:

17014

American (AMR)

AF:

0.200

AC:

3913

AN:

19568

Ashkenazi Jewish (ASJ)

AF:

0.118

AC:

1572

AN:

13302

East Asian (EAS)

AF:

0.0980

AC:

1818

AN:

18558

South Asian (SAS)

AF:

0.133

AC:

5357

AN:

40282

European-Finnish (FIN)

AF:

0.0647

AC:

1775

AN:

27442

Middle Eastern (MID)

AF:

0.109

AC:

210

AN:

1934

European-Non Finnish (NFE)

AF:

0.0931

AC:

44814

AN:

481220

Other (OTH)

AF:

0.102

AC:

2793

AN:

27316

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.281

Heterozygous variant carriers

5501

11001

16502

22002

27503

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

1580

3160

4740

6320

7900

<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

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00147

AC:

116

AN:

79100

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

AN XY:

38030

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000748

AC:

AN:

24076

American (AMR)

AF:

0.00211

AC:

AN:

7110

Ashkenazi Jewish (ASJ)

AF:

0.00154

AC:

AN:

1942

East Asian (EAS)

AF:

0.00250

AC:

AN:

2802

South Asian (SAS)

AF:

0.00193

AC:

AN:

2076

European-Finnish (FIN)

AF:

0.00352

AC:

AN:

3688

Middle Eastern (MID)

AF:

0.00

AC:

AN:

180

European-Non Finnish (NFE)

AF:

0.00151

AC:

AN:

35730

Other (OTH)

AF:

0.00193

AC:

AN:

1034

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.251

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:

0.0203

Hom.:

ExAC

AF:

0.000731

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Aug 20, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Inborn genetic diseases

Benign:1

Mar 19, 2020

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

0.073

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.31

(source)

DANN

Benign

0.40

DEOGEN2

Benign

0.012

T;T

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.036

LIST_S2

Benign

0.28

T;T

MetaRNN

Benign

0.0026

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

.;L

PhyloP100

-0.89

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.65

N;N

REVEL

Benign

0.0060

Sift

Benign

0.32

T;T

Sift4G

Benign

0.16

T;T

Polyphen

0.0010

.;B

Vest4

0.12

MutPred

0.30

.;Gain of glycosylation at A92 (P = 0.0011);

MPC

0.66

ClinPred

0.00069

GERP RS

-6.6

Varity_R

0.051

gMVP

0.43

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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