22-23766225-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP5BS2

The ENST00000484558.3(CHCHD10):c.312C>G(p.Tyr104*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00291 in 1,556,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Y104Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0032 ( 0 hom. )

Consequence

CHCHD10
ENST00000484558.3 stop_gained

Scores

Clinical Significance

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

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: Likely_benign. The variant received -3 ACMG points.

PP5

Variant 22-23766225-G-C is Pathogenic according to our data. Variant chr22-23766225-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 565755.

BS2

High AC in GnomAd4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000484558.3. 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>G	p.Tyr104*	stop_gained	Exon 3 of 4	NP_998885.1
CHCHD10	NM_001301339.2		c.333C>G	p.Tyr111*	stop_gained	Exon 3 of 4	NP_001288268.1
CHCHD10	NR_125755.2		n.357C>G		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>G	p.Tyr104*	stop_gained	Exon 3 of 4	ENSP00000418428.3
CHCHD10	ENST00000401675.7	TSL:5	c.333C>G	p.Tyr111*	stop_gained	Exon 3 of 4	ENSP00000384973.3
CHCHD10	ENST00000520222.1	TSL:3	c.92C>G	p.Thr31Arg	missense	Exon 2 of 3	ENSP00000430042.1

Frequencies

GnomAD3 genomes

AF:

0.0000333

AC:

AN:

150208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000199

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000965

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000136

AC:

AN:

220022

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000947

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00322

AC:

4523

AN:

1406386

Hom.:

Cov.:

AF XY:

0.00299

AC XY:

2089

AN XY:

699386

show subpopulations

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

African (AFR)

AF:

0.00257

AC:

AN:

32340

American (AMR)

AF:

0.000166

AC:

AN:

42160

Ashkenazi Jewish (ASJ)

AF:

0.00161

AC:

AN:

25460

East Asian (EAS)

AF:

0.000313

AC:

AN:

38362

South Asian (SAS)

AF:

0.000744

AC:

AN:

83298

European-Finnish (FIN)

AF:

0.0000580

AC:

AN:

51714

Middle Eastern (MID)

AF:

0.00248

AC:

AN:

5250

European-Non Finnish (NFE)

AF:

0.00389

AC:

4160

AN:

1069264

Other (OTH)

AF:

0.00243

AC:

142

AN:

58538

⚠️ 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: 0.243

Heterozygous variant carriers

714

1428

2143

2857

3571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

226

452

678

904

1130

<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:

0.0000333

AC:

AN:

150322

Hom.:

Cov.:

AF XY:

0.0000273

AC XY:

AN XY:

73276

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40894

American (AMR)

AF:

0.000199

AC:

AN:

15070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

4988

South Asian (SAS)

AF:

0.00

AC:

AN:

4712

European-Finnish (FIN)

AF:

0.0000965

AC:

AN:

10362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000148

AC:

AN:

67558

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.395

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.:

26412

ExAC

AF:

0.00000830

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

0.079

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Benign

-0.039

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.35

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.96

PhyloP100

0.094

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.32

Vest4

0.28

MutPred

0.088

Loss of glycosylation at T31 (P = 0.01)

MVP

0.14

ClinPred

0.98

GERP RS

-5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=25/175

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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