rs1054055

Variant names:

• chr22-23765747-C-T
• rs1054055
• NM_182520.3:c.*15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001331041.2(C22orf15):​c.467C>T​(p.Thr156Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,550,786 control chromosomes in the GnomAD database, including 1,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (835 hom., cov: 33)
  • Exomes 𝑓: 0.0059 (737 hom.)
• Consequence: C22orf15 NM_001331041.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0410
• Publications: 6 publications found

Genes affected

C22orf15 (HGNC:15558): (chromosome 22 open reading frame 15)

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020511746).
• BP6: Variant 22-23765747-C-T is Benign according to our data. Variant chr22-23765747-C-T is described in ClinVar as Benign. ClinVar VariationId is 1238466.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.195 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001331041.2. 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
	C22orf15	NM_182520.3	MANE Select	c.*15C>T		3_prime_UTR	Exon 6 of 6	NP_872326.2	Q8WYQ4-1
	C22orf15	NM_001331041.2		c.467C>T	p.Thr156Ile	missense	Exon 6 of 6	NP_001317970.1	F8W7S3
	C22orf15	NM_001376903.1		c.*19C>T		3_prime_UTR	Exon 6 of 6	NP_001363832.1	Q8WYQ4-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C22orf15	ENST00000402217.8	TSL:2 MANE Select	c.*15C>T		3_prime_UTR	Exon 6 of 6	ENSP00000384965.4	Q8WYQ4-1
	C22orf15	ENST00000382821.3	TSL:1	c.*19C>T		3_prime_UTR	Exon 6 of 6	ENSP00000372271.3	Q8WYQ4-2
	C22orf15	ENST00000305199.9	TSL:3	c.467C>T	p.Thr156Ile	missense	Exon 6 of 6	ENSP00000305096.5	F8W7S3

Frequencies

GnomAD3 genomes AF: 0.0572 AC: 8705 AN: 152148 Hom.: 833 Cov.: 33

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0212

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000706

Gnomad OTH AF: 0.0416

GnomAD2 exomes AF: 0.0126 AC: 1967 AN: 155640 AF XY: 0.00981

Gnomad AFR exome AF: 0.206

Gnomad AMR exome AF: 0.0107

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000815

Gnomad OTH exome AF: 0.00527

GnomAD4 exome AF: 0.00588 AC: 8225 AN: 1398520 Hom.: 737 Cov.: 34 AF XY: 0.00507 AC XY: 3494 AN XY: 689678

African (AFR) AF: 0.207 AC: 6534 AN: 31584

American (AMR) AF: 0.0122 AC: 435 AN: 35626

Ashkenazi Jewish (ASJ) AF: 0.0000796 AC: 2 AN: 25122

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.000266 AC: 21 AN: 79066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49178

Middle Eastern (MID) AF: 0.00653 AC: 37 AN: 5664

European-Non Finnish (NFE) AF: 0.000403 AC: 435 AN: 1078590

Other (OTH) AF: 0.0131 AC: 761 AN: 57964

GnomAD4 genome AF: 0.0573 AC: 8719 AN: 152266 Hom.: 835 Cov.: 33 AF XY: 0.0547 AC XY: 4072 AN XY: 74450

African (AFR) AF: 0.199 AC: 8250 AN: 41526

American (AMR) AF: 0.0212 AC: 324 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00124 AC: 6 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000706 AC: 48 AN: 68022

Other (OTH) AF: 0.0412 AC: 87 AN: 2112

Alfa AF: 0.0407 Hom.: 544

Bravo AF: 0.0651

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0137 AC: 554

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	1.1
DANN	Benign	0.87
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.26	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.041
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.010
Sift	Pathogenic	0.0	D
Vest4		0.057
ClinPred		0.0018	T
GERP RS		-0.16
gMVP		0.24
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1054055; hg19: chr22-24107934;