22-23767592-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_213720.3(CHCHD10):​c.43C>A​(p.Arg15Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000933 in 1,071,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as no classification for the single variant (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: CHCHD10 NM_213720.3 missense, splice_region
• Scores: Splicing: ADA: 0.9443
• 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 2 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=0.2360399).

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>A	p.Arg15Ser	missense splice_region	Exon 2 of 4	NP_998885.1
	CHCHD10	NM_001301339.2		c.43C>A	p.Arg15Ser	missense splice_region	Exon 2 of 4	NP_001288268.1
	CHCHD10	NR_125755.2		n.140-52C>A		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>A	p.Arg15Ser	missense splice_region	Exon 2 of 4	ENSP00000418428.3
	CHCHD10	ENST00000401675.7	TSL:5	c.43C>A	p.Arg15Ser	missense splice_region	Exon 2 of 4	ENSP00000384973.3
	CHCHD10	ENST00000520222.1	TSL:3	c.41+242C>A		intron	N/A	ENSP00000430042.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.33e-7 AC: 1 AN: 1071338 Hom.: 0 Cov.: 16 AF XY: 0.00000191 AC XY: 1 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: 0.00000114 AC: 1 AN: 874236

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	0.15
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Benign	0.020	T
Eigen	Benign	0.053
Eigen_PC	Benign	0.040
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.4
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.27
Sift	Benign	0.11	T
Sift4G	Benign	0.10	T
Polyphen		0.99	D
Vest4		0.28
MutPred		0.32		Gain of phosphorylation at R15 (P = 0.0013)
MVP		0.29
MPC		0.57
ClinPred		0.74	D
GERP RS		4.0
PromoterAI		-0.016	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.1
Varity_R		0.28
gMVP		0.37
Mutation Taster		=48/52	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.79		Position offset: -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;