NM_213720.3:c.274G>C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_213720.3(CHCHD10):​c.274G>C​(p.Ala92Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). 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 0.0015 (0 hom., cov: 22)
  • Exomes 𝑓: 0.098 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.886
• Publications: 4 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025873482).
• BP6: Variant 22-23766263-C-G is Benign according to our data. Variant chr22-23766263-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 1259100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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>C	p.Ala92Pro	missense	Exon 3 of 4	NP_998885.1	Q8WYQ3
	CHCHD10	NM_001301339.2		c.295G>C	p.Ala99Pro	missense	Exon 3 of 4	NP_001288268.1	B5MBW9
	CHCHD10	NR_125755.2		n.319G>C		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>C	p.Ala92Pro	missense	Exon 3 of 4	ENSP00000418428.3	Q8WYQ3
	CHCHD10	ENST00000878118.1		c.337G>C	p.Ala113Pro	missense	Exon 3 of 4	ENSP00000548177.1
	CHCHD10	ENST00000878120.1		c.274G>C	p.Ala92Pro	missense	Exon 3 of 4	ENSP00000548179.1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 116 AN: 79090 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000749

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00211

Gnomad ASJ AF: 0.00154

Gnomad EAS AF: 0.00249

Gnomad SAS AF: 0.00192

Gnomad FIN AF: 0.00352

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.00195

GnomAD2 exomes AF: 0.0831 AC: 6718 AN: 80812 AF XY: 0.0786

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.0902

Gnomad EAS exome AF: 0.118

Gnomad FIN exome AF: 0.0413

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.111

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0980 AC: 63389 AN: 646636 Hom.: 0 Cov.: 24 AF XY: 0.0985 AC XY: 31896 AN XY: 323752

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

African (AFR) AF: 0.0668 AC: 1137 AN: 17014

American (AMR) AF: 0.200 AC: 3913 AN: 19568

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 1572 AN: 13302

East Asian (EAS) AF: 0.0980 AC: 1818 AN: 18558

South Asian (SAS) AF: 0.133 AC: 5357 AN: 40282

European-Finnish (FIN) AF: 0.0647 AC: 1775 AN: 27442

Middle Eastern (MID) AF: 0.109 AC: 210 AN: 1934

European-Non Finnish (NFE) AF: 0.0931 AC: 44814 AN: 481220

Other (OTH) AF: 0.102 AC: 2793 AN: 27316

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00147 AC: 116 AN: 79100 Hom.: 0 Cov.: 22 AF XY: 0.00147 AC XY: 56 AN XY: 38030

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

African (AFR) AF: 0.000748 AC: 18 AN: 24076

American (AMR) AF: 0.00211 AC: 15 AN: 7110

Ashkenazi Jewish (ASJ) AF: 0.00154 AC: 3 AN: 1942

East Asian (EAS) AF: 0.00250 AC: 7 AN: 2802

South Asian (SAS) AF: 0.00193 AC: 4 AN: 2076

European-Finnish (FIN) AF: 0.00352 AC: 13 AN: 3688

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 180

European-Non Finnish (NFE) AF: 0.00151 AC: 54 AN: 35730

Other (OTH) AF: 0.00193 AC: 2 AN: 1034

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0203 Hom.: 0

ExAC AF: 0.000731 AC: 47

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.31
DANN	Benign	0.40
DEOGEN2	Benign	0.012	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.89
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.0060
Sift	Benign	0.32	T
Sift4G	Benign	0.16	T
Polyphen		0.0010	B
Vest4		0.12
MutPred		0.30		Gain of glycosylation at A92 (P = 0.0011)
MPC		0.66
ClinPred		0.00069	T
GERP RS		-6.6
Varity_R		0.051
gMVP		0.43
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs374353973; hg19: chr22-24108450; COSMIC: COSV59417527; COSMIC: COSV59417527;