Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_213720.3(CHCHD10):c.312C>T(p.Tyr104Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.801 in 1,577,154 control chromosomes in the GnomAD database, including 506,344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 48248 hom., cov: 24)

Exomes 𝑓: 0.80 ( 458096 hom. )

Consequence

CHCHD10
NM_213720.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.0940

Publications

22 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.019759E-6).

BP6

Variant 22-23766225-G-A is Benign according to our data. Variant chr22-23766225-G-A is described in ClinVar as Benign. ClinVar VariationId is 379953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.094 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.826 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213720.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHCHD10	NM_213720.3	MANE Select	c.312C>T	p.Tyr104Tyr	synonymous	Exon 3 of 4	NP_998885.1
CHCHD10	NM_001301339.2		c.333C>T	p.Tyr111Tyr	synonymous	Exon 3 of 4	NP_001288268.1
CHCHD10	NR_125755.2		n.357C>T		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CHCHD10	ENST00000484558.3	TSL:1 MANE Select	c.312C>T	p.Tyr104Tyr	synonymous	Exon 3 of 4	ENSP00000418428.3
CHCHD10	ENST00000520222.1	TSL:3	c.92C>T	p.Thr31Met	missense	Exon 2 of 3	ENSP00000430042.1
CHCHD10	ENST00000401675.7	TSL:5	c.333C>T	p.Tyr111Tyr	synonymous	Exon 3 of 4	ENSP00000384973.3

Frequencies

GnomAD3 genomes

AF:

0.799

AC:

119979

AN:

150144

Hom.:

48232

Cov.:

show subpopulations

Gnomad AFR

AF:

0.765

Gnomad AMI

AF:

0.751

Gnomad AMR

AF:

0.832

Gnomad ASJ

AF:

0.840

Gnomad EAS

AF:

0.638

Gnomad SAS

AF:

0.593

Gnomad FIN

AF:

0.834

Gnomad MID

AF:

0.848

Gnomad NFE

AF:

0.832

Gnomad OTH

AF:

0.793

GnomAD2 exomes

AF:

0.779

AC:

171489

AN:

220022

AF XY:

0.773

show subpopulations

Gnomad AFR exome

AF:

0.759

Gnomad AMR exome

AF:

0.811

Gnomad ASJ exome

AF:

0.840

Gnomad EAS exome

AF:

0.626

Gnomad FIN exome

AF:

0.833

Gnomad NFE exome

AF:

0.829

Gnomad OTH exome

AF:

0.799

GnomAD4 exome

AF:

0.801

AC:

1143599

AN:

1426896

Hom.:

458096

Cov.:

AF XY:

0.797

AC XY:

564634

AN XY:

708842

show subpopulations

African (AFR)

AF:

0.747

AC:

24426

AN:

32686

American (AMR)

AF:

0.816

AC:

34405

AN:

42162

Ashkenazi Jewish (ASJ)

AF:

0.833

AC:

21333

AN:

25614

East Asian (EAS)

AF:

0.627

AC:

24089

AN:

38426

South Asian (SAS)

AF:

0.610

AC:

50887

AN:

83464

European-Finnish (FIN)

AF:

0.827

AC:

42807

AN:

51748

Middle Eastern (MID)

AF:

0.756

AC:

3976

AN:

5262

European-Non Finnish (NFE)

AF:

0.822

AC:

894816

AN:

1088348

Other (OTH)

AF:

0.792

AC:

46860

AN:

59186

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

9550

19100

28650

38200

47750

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20536

41072

61608

82144

102680

<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:

0.799

AC:

120034

AN:

150258

Hom.:

48248

Cov.:

AF XY:

0.794

AC XY:

58159

AN XY:

73238

show subpopulations

African (AFR)

AF:

0.765

AC:

31252

AN:

40870

American (AMR)

AF:

0.832

AC:

12540

AN:

15066

Ashkenazi Jewish (ASJ)

AF:

0.840

AC:

2909

AN:

3462

East Asian (EAS)

AF:

0.638

AC:

3173

AN:

4976

South Asian (SAS)

AF:

0.593

AC:

2791

AN:

4710

European-Finnish (FIN)

AF:

0.834

AC:

8638

AN:

10356

Middle Eastern (MID)

AF:

0.847

AC:

249

AN:

294

European-Non Finnish (NFE)

AF:

0.832

AC:

56174

AN:

67544

Other (OTH)

AF:

0.785

AC:

1635

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.537

Heterozygous variant carriers

1121

2242

3363

4484

5605

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

850

1700

2550

3400

4250

<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:

0.808

Hom.:

26412

Bravo

AF:

0.798

TwinsUK

AF:

0.848

AC:

3143

ALSPAC

AF:

0.848

AC:

3269

ESP6500AA

AF:

0.751

AC:

3311

ESP6500EA

AF:

0.832

AC:

7159

ExAC

AF:

0.758

AC:

91429

Asia WGS

AF:

0.646

AC:

2245

AN:

3474

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

Lower motor neuron syndrome with late-adult onset (2)

Autosomal dominant mitochondrial myopathy with exercise intolerance (1)

Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (1)

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 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.6

(source)

DANN

Benign

0.95

Eigen

Benign

-0.49

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.41

MetaRNN

Benign

0.0000010

MetaSVM

Benign

-1.0

PhyloP100

0.094

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.49

Vest4

0.15

ClinPred

0.070

GERP RS

-5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=96/4

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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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rs9153

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over