rs111677724

chr22-23766251-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_213720.3(CHCHD10):c.286C>A(p.Pro96Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0101 in 1,552,410 control chromosomes in the GnomAD database, including 1,343 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P96H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.053 (724 hom., cov: 28)
  • Exomes 𝑓: 0.0055 (619 hom.)
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 2.66

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=0.0017307997).
• BP6: Variant 22-23766251-G-T is Benign according to our data. Variant chr22-23766251-G-T is described in ClinVar as [Benign]. Clinvar id is 473424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23766251-G-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHCHD10	NM_213720.3	c.286C>A	p.Pro96Thr	missense_variant	3/4	ENST00000484558.3
CHCHD10	NM_001301339.2	c.307C>A	p.Pro103Thr	missense_variant	3/4
CHCHD10	NR_125755.2	n.331C>A		non_coding_transcript_exon_variant	3/4
CHCHD10	NR_125756.2	n.164C>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD10	ENST00000484558.3	c.286C>A	p.Pro96Thr	missense_variant	3/4	1	NM_213720.3	P1

Frequencies

GnomAD3 genomes AF: 0.0526 AC: 7967 AN: 151524 Hom.: 723 Cov.: 28

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000633

Gnomad OTH AF: 0.0389

GnomAD3 exomes AF: 0.0132 AC: 2102 AN: 159398 Hom.: 168 AF XY: 0.0102 AC XY: 873 AN XY: 85596

Gnomad AFR exome AF: 0.208

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.000118

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000129

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000827

Gnomad OTH exome AF: 0.00471

GnomAD4 exome AF: 0.00547 AC: 7657 AN: 1400780 Hom.: 619 Cov.: 35 AF XY: 0.00471 AC XY: 3259 AN XY: 691798

Gnomad4 AFR exome AF: 0.192

Gnomad4 AMR exome AF: 0.0116

Gnomad4 ASJ exome AF: 0.000119

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000226

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000347

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0526 AC: 7981 AN: 151630 Hom.: 724 Cov.: 28 AF XY: 0.0505 AC XY: 3741 AN XY: 74100

Gnomad4 AFR AF: 0.183

Gnomad4 AMR AF: 0.0196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00105

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000633

Gnomad4 OTH AF: 0.0385

Alfa AF: 0.0243 Hom.: 138

Bravo AF: 0.0599

ESP6500AA AF: 0.175 AC: 764

ESP6500EA AF: 0.00118 AC: 10

ExAC AF: 0.0156 AC: 1681

Asia WGS AF: 0.00838 AC: 29 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 01, 2018

This variant is associated with the following publications: (PMID: 29519717) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	23
Dann	Benign	0.97
DEOGEN2	Benign	0.029	T;T
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.60	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.000016	P;P;P
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.070
Sift	Benign	0.39	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.90	.;P
Vest4		0.19
MPC		1.2
ClinPred		0.023	T
GERP RS		4.2
Varity_R		0.084
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs111677724; hg19: chr22-24108438;