rs551521196

Positions:

chr22-23767535-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_213720.3(CHCHD10):c.100C>T(p.Pro34Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00406 in 1,451,942 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0043 ( 17 hom. )

Consequence

CHCHD10
NM_213720.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 1.56

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011065036).

BP6

Variant 22-23767535-G-A is Benign according to our data. Variant chr22-23767535-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 204291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23767535-G-A is described in UniProt as null. Variant chr22-23767535-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 349 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD10	NM_213720.3 link	c.100C>T	p.Pro34Ser	missense_variant	2/4	ENST00000484558.3	NP_998885.1	Q8WYQ3
CHCHD10	NM_001301339.2 link	c.100C>T	p.Pro34Ser	missense_variant	2/4		NP_001288268.1	Q8WYQ3B5MBW9
CHCHD10	NR_125755.2 link	n.145C>T		non_coding_transcript_exon_variant	2/4
CHCHD10	NR_125756.2 link	n.139+299C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CHCHD10	ENST00000484558.3 link	c.100C>T	p.Pro34Ser	missense_variant	2/4	1	NM_213720.3	ENSP00000418428.3	Q8WYQ3
CHCHD10	ENST00000401675.7 link	c.100C>T	p.Pro34Ser	missense_variant	2/4	5		ENSP00000384973.3	B5MBW9
CHCHD10	ENST00000520222.1 link	c.41+299C>T		intron_variant		3		ENSP00000430042.1	E5RH03
CHCHD10	ENST00000517886.1 link	n.47C>T		non_coding_transcript_exon_variant	2/4	3		ENSP00000429976.1	E5RGN4

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

349

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00273

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00381

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00277

AC:

176

AN:

63606

Hom.:

AF XY:

0.00249

AC XY:

AN XY:

37762

show subpopulations

Gnomad AFR exome

AF:

0.00110

Gnomad AMR exome

AF:

0.00202

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000753

Gnomad FIN exome

AF:

0.00444

Gnomad NFE exome

AF:

0.00501

Gnomad OTH exome

AF:

0.000619

GnomAD4 exome

AF:

0.00426

AC:

5542

AN:

1299678

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

2603

AN XY:

638006

show subpopulations

Gnomad4 AFR exome

AF:

0.000658

Gnomad4 AMR exome

AF:

0.00109

Gnomad4 ASJ exome

AF:

0.0000917

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000429

Gnomad4 FIN exome

AF:

0.00248

Gnomad4 NFE exome

AF:

0.00507

Gnomad4 OTH exome

AF:

0.00281

GnomAD4 genome

AF:

0.00229

AC:

349

AN:

152264

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

145

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.000962

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00273

Gnomad4 NFE

AF:

0.00381

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00180

Hom.:

Bravo

AF:

0.00235

ExAC

AF:

0.00113

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	CHCHD10: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2021	This variant is associated with the following publications: (PMID: 25155093, 27056076, 25576308, 26344877, 26152333, 26362909, 26362910, 25953780, 25726362, 25833818, 26666268, 27810918, 28069311, 29315381, 28108040, 27095681, 30014597, 27578015, 27077676, 30293881, 29525180, 29789341, 32651855) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Lower motor neuron syndrome with late-adult onset

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 22, 2021

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. -

CHCHD10-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 07, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Autosomal dominant mitochondrial myopathy with exercise intolerance

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

May 04, 2023

European Non-Finnish population allele frequency is 0.3428% (rs551521196, 259/67998 alleles, 0 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -

Frontotemporal dementia and/or amyotrophic lateral sclerosis 2

Other:1

not provided, no classification provided

literature only

GeneReviews

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.83

DEOGEN2

Benign

0.022

T;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.62

T;T

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.011

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;L

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.62

Sift

Benign

0.24

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.056

.;B

Vest4

0.36

MVP

0.13

MPC

0.51

ClinPred

0.012

GERP RS

1.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.2

Varity_R

0.070

gMVP

0.36

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

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