rs551521196

chr22-23767535-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P34L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0043 (17 hom.)
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 1.56

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]

ACMG classification

Verdict is Benign. Variant got -20 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].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00229 (349/152264) while in subpopulation NFE AF= 0.00381 (259/67988). AF 95% confidence interval is 0.00343. There are 1 homozygotes in gnomad4. There are 145 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 349 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD10	ENST00000484558.3	c.100C>T	p.Pro34Ser	missense_variant	2/4	1	NM_213720.3	P1
CHCHD10	ENST00000401675.7	c.100C>T	p.Pro34Ser	missense_variant	2/4	5
CHCHD10	ENST00000520222.1	c.41+299C>T		intron_variant		3
CHCHD10	ENST00000517886.1	c.47C>T	p.Pro16Leu	missense_variant, NMD_transcript_variant	2/4	3

Frequencies

GnomAD3 genomes AF: 0.00229 AC: 349 AN: 152156 Hom.: 1 Cov.: 33

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.: 1 AF XY: 0.00249 AC XY: 94 AN XY: 37762

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.: 17 Cov.: 35 AF XY: 0.00408 AC XY: 2603 AN XY: 638006

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.: 1 Cov.: 33 AF XY: 0.00195 AC XY: 145 AN XY: 74446

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.: 2

Bravo AF: 0.00235

ExAC AF: 0.00113 AC: 95

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CHCHD10: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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, criteria provided, single submitter

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

Invitae

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	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Benign	0.83
DEOGEN2	Benign	0.022	T;T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.62	T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
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	T
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

Other links and lift over

dbSNP: rs551521196; hg19: chr22-24109722;