rs781304084

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_213720.3(CHCHD10):c.190G>C(p.Val64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V64I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CHCHD10
NM_213720.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.15

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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_213720.3

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21916679).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CHCHD10	NM_213720.3 link	c.190G>C	p.Val64Leu	missense_variant	Exon 2 of 4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2 link	c.190G>C	p.Val64Leu	missense_variant	Exon 2 of 4		NP_001288268.1
CHCHD10	NR_125755.2 link	n.235G>C		non_coding_transcript_exon_variant	Exon 2 of 4
CHCHD10	NR_125756.2 link	n.139+389G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CHCHD10	ENST00000484558.3 link	c.190G>C	p.Val64Leu	missense_variant	Exon 2 of 4	1	NM_213720.3	ENSP00000418428.3
CHCHD10	ENST00000401675.7 link	c.190G>C	p.Val64Leu	missense_variant	Exon 2 of 4	5		ENSP00000384973.3
CHCHD10	ENST00000517886.1 link	n.137G>C		non_coding_transcript_exon_variant	Exon 2 of 4	3		ENSP00000429976.1
CHCHD10	ENST00000520222.1 link	c.41+389G>C		intron_variant	Intron 1 of 2	3		ENSP00000430042.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000445

AC:

AN:

224770

AF XY:

0.00000805

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000138

AC:

AN:

1451944

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721788

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33172

American (AMR)

AF:

0.00

AC:

AN:

44136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25898

East Asian (EAS)

AF:

0.00

AC:

AN:

39364

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4266

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1109184

Other (OTH)

AF:

0.00

AC:

AN:

59822

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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

Cov.:

ExAC

AF:

0.00000836

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Pathogenic

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.043

T;T

Eigen

Benign

0.16

Eigen_PC

Benign

0.035

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.92

D;D

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.80

MutationAssessor

Benign

0.0

.;M

PhyloP100

1.1

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.12

Sift

Uncertain

0.013

D;D

Sift4G

Benign

0.10

T;T

Vest4

0.27

ClinPred

0.82

GERP RS

2.6

PromoterAI

-0.18

Neutral

(source)

Varity_R

0.17

gMVP

0.58

Mutation Taster

=80/20

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over