NM_213720.3:c.274G>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 1259100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23766263-C-G is described in Lovd as [Likely_benign].

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:

0.00

AC:

116

AN:

79090

Hom.:

Cov.:

FAILED QC

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

GnomAD3 exomes

AF:

0.0831

AC:

6718

AN:

80812

Hom.:

AF XY:

0.0786

AC XY:

3548

AN XY:

45124

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 SAS exome

AF:

0.0793

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

Gnomad4 AFR exome

AF:

0.0668

Gnomad4 AMR exome

AF:

0.200

Gnomad4 ASJ exome

AF:

0.118

Gnomad4 EAS exome

AF:

0.0980

Gnomad4 SAS exome

AF:

0.133

Gnomad4 FIN exome

AF:

0.0647

Gnomad4 NFE exome

AF:

0.0931

Gnomad4 OTH exome

AF:

0.102

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

Gnomad4 AFR

AF:

0.000748

Gnomad4 AMR

AF:

0.00211

Gnomad4 ASJ

AF:

0.00154

Gnomad4 EAS

AF:

0.00250

Gnomad4 SAS

AF:

0.00193

Gnomad4 FIN

AF:

0.00352

Gnomad4 NFE

AF:

0.00151

Gnomad4 OTH

AF:

0.00193

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

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

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over