NM_213720.3:c.197G>T

Variant names:

• chr22-23767438-C-A
• rs730880031
• NM_213720.3:c.197G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3 PP5_Moderate

The NM_213720.3(CHCHD10):​c.197G>T​(p.Gly66Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,452,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G66S) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:3 O:1
• Conservation: PhyloP100: 5.76
• Publications: 39 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: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_213720.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-23767439-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 655998.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833
• PP5: Variant 22-23767438-C-A is Pathogenic according to our data. Variant chr22-23767438-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 180221.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD10	NM_213720.3	c.197G>T	p.Gly66Val	missense_variant	Exon 2 of 4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2	c.197G>T	p.Gly66Val	missense_variant	Exon 2 of 4		NP_001288268.1
CHCHD10	NR_125755.2	n.242G>T		non_coding_transcript_exon_variant	Exon 2 of 4
CHCHD10	NR_125756.2	n.139+396G>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3	c.197G>T	p.Gly66Val	missense_variant	Exon 2 of 4	1	NM_213720.3	ENSP00000418428.3
CHCHD10	ENST00000401675.7	c.197G>T	p.Gly66Val	missense_variant	Exon 2 of 4	5		ENSP00000384973.3
CHCHD10	ENST00000517886.1	n.144G>T		non_coding_transcript_exon_variant	Exon 2 of 4	3		ENSP00000429976.1
CHCHD10	ENST00000520222.1	c.41+396G>T		intron_variant	Intron 1 of 2	3		ENSP00000430042.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000176 AC: 4 AN: 226942 AF XY: 0.00000798

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000202

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1452808 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 722274

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33224

American (AMR) AF: 0.00 AC: 0 AN: 44220

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39400

South Asian (SAS) AF: 0.00 AC: 0 AN: 84932

European-Finnish (FIN) AF: 0.0000583 AC: 3 AN: 51426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4268

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1109538

Other (OTH) AF: 0.00 AC: 0 AN: 59862

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.066232), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000833 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lower motor neuron syndrome with late-adult onset Pathogenic:2

Jun 01, 2022

Solve-RD Consortium

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Jan 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 28, 2023

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal dominant mitochondrial myopathy with exercise intolerance Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Founder variant in Finnish population, associated with late-onset SMN (spinal motor neuropathy) or SMAJ (spinal muscular atrophy, Jokela type) and axonal CMT (Charcot-Marie-Tooth) disease -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Uncertain	2.5	.;M
PhyloP100		5.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-8.5	D;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.86
MutPred		0.48		Gain of helix (P = 0.0078);Gain of helix (P = 0.0078);
MVP		0.36
MPC		1.6
ClinPred		0.99	D
GERP RS		3.7
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.91
gMVP		0.74
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs730880031; hg19: chr22-24109625;