rs200831077

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_213720.3(CHCHD10):c.136G>T(p.Ala46Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000691 in 1,556,750 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts 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. A46D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 7 hom., cov: 33)

Exomes 𝑓: 0.00035 ( 5 hom. )

Consequence

CHCHD10
NM_213720.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.69

Publications

0 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008496523).

BP6

Variant 22-23767499-C-A is Benign according to our data. Variant chr22-23767499-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473420.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAd4 at 589 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHCHD10	NM_213720.3 link	c.136G>T	p.Ala46Ser	missense_variant	Exon 2 of 4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2 link	c.136G>T	p.Ala46Ser	missense_variant	Exon 2 of 4		NP_001288268.1
CHCHD10	NR_125755.2 link	n.181G>T		non_coding_transcript_exon_variant	Exon 2 of 4
CHCHD10	NR_125756.2 link	n.139+335G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CHCHD10	ENST00000484558.3 link	c.136G>T	p.Ala46Ser	missense_variant	Exon 2 of 4	1	NM_213720.3	ENSP00000418428.3
CHCHD10	ENST00000401675.7 link	c.136G>T	p.Ala46Ser	missense_variant	Exon 2 of 4	5		ENSP00000384973.3
CHCHD10	ENST00000517886.1 link	n.83G>T		non_coding_transcript_exon_variant	Exon 2 of 4	3		ENSP00000429976.1
CHCHD10	ENST00000520222.1 link	c.41+335G>T		intron_variant	Intron 1 of 2	3		ENSP00000430042.1

Frequencies

GnomAD3 genomes

AF:

0.00384

AC:

585

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0132

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00209

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:

0.0000294

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000686

AC:

109

AN:

158892

AF XY:

0.000482

show subpopulations

Gnomad AFR exome

AF:

0.0145

Gnomad AMR exome

AF:

0.000652

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000154

Gnomad OTH exome

AF:

0.000240

GnomAD4 exome

AF:

0.000347

AC:

487

AN:

1404468

Hom.:

Cov.:

AF XY:

0.000275

AC XY:

191

AN XY:

695174

show subpopulations

African (AFR)

AF:

0.0122

AC:

371

AN:

30434

American (AMR)

AF:

0.000982

AC:

AN:

38678

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24842

East Asian (EAS)

AF:

0.00

AC:

AN:

35460

South Asian (SAS)

AF:

0.0000617

AC:

AN:

81016

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46738

Middle Eastern (MID)

AF:

0.000244

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.0000101

AC:

AN:

1085288

Other (OTH)

AF:

0.00105

AC:

AN:

57912

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00387

AC:

589

AN:

152282

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

264

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0132

AC:

549

AN:

41566

American (AMR)

AF:

0.00209

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68008

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

110

138

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00115

Hom.:

Bravo

AF:

0.00430

ESP6500AA

AF:

0.00949

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000792

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

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 28, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.038

T;T

Eigen

Benign

0.12

Eigen_PC

Benign

0.099

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.85

T;T

MetaRNN

Benign

0.0085

T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.2

.;M

PhyloP100

4.7

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.15

Sift

Benign

0.048

D;T

Sift4G

Benign

0.061

T;T

Polyphen

1.0

.;D

Vest4

0.54

MVP

0.16

MPC

0.97

ClinPred

0.044

GERP RS

2.6

PromoterAI

0.0060

Neutral

(source)

Varity_R

0.15

gMVP

0.57

Mutation Taster

=63/37

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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