22-23767592-G-C

Variant names:

• chr22-23767592-G-C
• rs730880032
• NM_213720.3:c.43C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_213720.3(CHCHD10):​c.43C>G​(p.Arg15Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHCHD10 NM_213720.3 missense, splice_region
• Scores: Splicing: ADA: 0.8876
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• Publications: 10 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-23767591-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 180220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.33955532).

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.43C>G	p.Arg15Gly	missense splice_region	Exon 2 of 4	NP_998885.1
	CHCHD10	NM_001301339.2		c.43C>G	p.Arg15Gly	missense splice_region	Exon 2 of 4	NP_001288268.1
	CHCHD10	NR_125755.2		n.140-52C>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	ENST00000484558.3	TSL:1 MANE Select	c.43C>G	p.Arg15Gly	missense splice_region	Exon 2 of 4	ENSP00000418428.3
	CHCHD10	ENST00000401675.7	TSL:5	c.43C>G	p.Arg15Gly	missense splice_region	Exon 2 of 4	ENSP00000384973.3
	CHCHD10	ENST00000520222.1	TSL:3	c.41+242C>G		intron	N/A	ENSP00000430042.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1071340 Hom.: 0 Cov.: 16 AF XY: 0.00 AC XY: 0 AN XY: 522302

African (AFR) AF: 0.00 AC: 0 AN: 21034

American (AMR) AF: 0.00 AC: 0 AN: 9418

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15386

East Asian (EAS) AF: 0.00 AC: 0 AN: 26852

South Asian (SAS) AF: 0.00 AC: 0 AN: 47062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3056

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 874238

Other (OTH) AF: 0.00 AC: 0 AN: 44750

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.011	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Benign	0.93
DEOGEN2	Benign	0.071	T
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		1.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.36
Sift	Benign	0.040	D
Sift4G	Uncertain	0.019	D
Polyphen		0.99	D
Vest4		0.27
MutPred		0.32		Loss of methylation at R15 (P = 0.0089)
MVP		0.35
MPC		0.65
ClinPred		0.88	D
GERP RS		4.0
PromoterAI		0.092	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.1
Varity_R		0.34
gMVP		0.39
Mutation Taster		=49/51	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.89
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.010		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: rs730880032; hg19: chr22-24109779;