rs111677724

Variant names:

• chr22-23766251-G-T
• rs111677724
• NM_213720.3:c.286C>A

Variant summary

Our verdict is Benign. The variant received -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. 12/21 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:3
• Conservation: PhyloP100: 2.66
• Publications: 9 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 473424.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213720.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	NM_213720.3	MANE Select	c.286C>A	p.Pro96Thr	missense	Exon 3 of 4	NP_998885.1
	CHCHD10	NM_001301339.2		c.307C>A	p.Pro103Thr	missense	Exon 3 of 4	NP_001288268.1
	CHCHD10	NR_125755.2		n.331C>A		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	ENST00000484558.3	TSL:1 MANE Select	c.286C>A	p.Pro96Thr	missense	Exon 3 of 4	ENSP00000418428.3
	CHCHD10	ENST00000401675.7	TSL:5	c.307C>A	p.Pro103Thr	missense	Exon 3 of 4	ENSP00000384973.3
	CHCHD10	ENST00000520222.1	TSL:3	c.66C>A	p.Ser22Arg	missense	Exon 2 of 3	ENSP00000430042.1

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

GnomAD2 exomes AF: 0.0132 AC: 2102 AN: 159398 AF XY: 0.0102

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 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

African (AFR) AF: 0.192 AC: 6107 AN: 31834

American (AMR) AF: 0.0116 AC: 424 AN: 36452

Ashkenazi Jewish (ASJ) AF: 0.000119 AC: 3 AN: 25186

East Asian (EAS) AF: 0.00 AC: 0 AN: 36106

South Asian (SAS) AF: 0.000226 AC: 18 AN: 79690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48314

Middle Eastern (MID) AF: 0.00666 AC: 28 AN: 4202

European-Non Finnish (NFE) AF: 0.000347 AC: 375 AN: 1080948

Other (OTH) AF: 0.0121 AC: 702 AN: 58048

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

African (AFR) AF: 0.183 AC: 7549 AN: 41240

American (AMR) AF: 0.0196 AC: 299 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00105 AC: 5 AN: 4782

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000633 AC: 43 AN: 67878

Other (OTH) AF: 0.0385 AC: 81 AN: 2104

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	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 (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.19
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	M
PhyloP100		2.7
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.070
Sift	Benign	0.39	T
Sift4G	Benign	0.59	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
Mutation Taster		=78/22	polymorphism (auto)

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

Other links and lift over

dbSNP: rs111677724; hg19: chr22-24108438;