22-23766263-C-A

Variant names:

• chr22-23766263-C-A
• rs374353973
• NM_213720.3:c.274G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_213720.3(CHCHD10):​c.274G>T​(p.Ala92Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000281 in 711,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 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. A92T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 22)
  • Exomes 𝑓: 0.0000028 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.886
• Publications: 0 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• frontotemporal dementia and/or amyotrophic lateral sclerosis 2

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• lower motor neuron syndrome with late-adult onset

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)
• 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

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	NM_213720.3	MANE Select	c.274G>T	p.Ala92Ser	missense	Exon 3 of 4	NP_998885.1	Q8WYQ3
	CHCHD10	NM_001301339.2		c.295G>T	p.Ala99Ser	missense	Exon 3 of 4	NP_001288268.1	B5MBW9
	CHCHD10	NR_125755.2		n.319G>T		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	ENST00000484558.3	TSL:1 MANE Select	c.274G>T	p.Ala92Ser	missense	Exon 3 of 4	ENSP00000418428.3	Q8WYQ3
	CHCHD10	ENST00000878118.1		c.337G>T	p.Ala113Ser	missense	Exon 3 of 4	ENSP00000548177.1
	CHCHD10	ENST00000878120.1		c.274G>T	p.Ala92Ser	missense	Exon 3 of 4	ENSP00000548179.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 79792 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000281 AC: 2 AN: 711244 Hom.: 0 Cov.: 24 AF XY: 0.00000281 AC XY: 1 AN XY: 356032

African (AFR) AF: 0.0000544 AC: 1 AN: 18382

American (AMR) AF: 0.00 AC: 0 AN: 21330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14952

East Asian (EAS) AF: 0.00 AC: 0 AN: 21834

South Asian (SAS) AF: 0.00 AC: 0 AN: 43822

European-Finnish (FIN) AF: 0.0000345 AC: 1 AN: 28986

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2166

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 529300

Other (OTH) AF: 0.00 AC: 0 AN: 30472

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 79792 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 38338

African (AFR) AF: 0.00 AC: 0 AN: 24162

American (AMR) AF: 0.00 AC: 0 AN: 7166

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1944

East Asian (EAS) AF: 0.00 AC: 0 AN: 2850

South Asian (SAS) AF: 0.00 AC: 0 AN: 2134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3752

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 194

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 36088

Other (OTH) AF: 0.00 AC: 0 AN: 1032

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.36
DANN	Benign	0.48
DEOGEN2	Benign	0.0091	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.27	T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.038	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.89
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.012
Sift	Benign	0.77	T
Sift4G	Benign	0.27	T
Polyphen		0.037	B
Vest4		0.13
MutPred		0.23		Gain of glycosylation at A92 (P = 0.0221)
MVP		0.030
MPC		0.77
ClinPred		0.030	T
GERP RS		-6.6
Varity_R		0.063
gMVP		0.37
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs374353973; hg19: chr22-24108450;