22-23767401-C-T

Variant names:

• chr22-23767401-C-T
• rs111527940
• NM_213720.3:c.234G>A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001301339.2(CHCHD10):​c.234G>A​(p.Ser78Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,608,354 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S78S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0073 (5 hom., cov: 33)
  • Exomes 𝑓: 0.011 (84 hom.)
• Consequence: CHCHD10 NM_001301339.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.35
• Publications: 6 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.04).
• BP6: Variant 22-23767401-C-T is Benign according to our data. Variant chr22-23767401-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 473423.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.35 with no splicing effect.
• BS2: High AC in GnomAd4 at 1113 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001301339.2. 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
	CHCHD10	NM_213720.3	MANE Select	c.234G>A	p.Ser78Ser	synonymous	Exon 2 of 4	NP_998885.1
	CHCHD10	NM_001301339.2		c.234G>A	p.Ser78Ser	synonymous	Exon 2 of 4	NP_001288268.1
	CHCHD10	NR_125755.2		n.279G>A		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD10	ENST00000484558.3	TSL:1 MANE Select	c.234G>A	p.Ser78Ser	synonymous	Exon 2 of 4	ENSP00000418428.3
	CHCHD10	ENST00000878118.1		c.297G>A	p.Ser99Ser	synonymous	Exon 2 of 4	ENSP00000548177.1
	CHCHD10	ENST00000878120.1		c.234G>A	p.Ser78Ser	synonymous	Exon 2 of 4	ENSP00000548179.1

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1113 AN: 152096 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.00217

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00760

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0114

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00740 AC: 1744 AN: 235754 AF XY: 0.00753

Gnomad AFR exome AF: 0.00225

Gnomad AMR exome AF: 0.00436

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.0000566

Gnomad FIN exome AF: 0.00751

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00950

GnomAD4 exome AF: 0.0106 AC: 15501 AN: 1456140 Hom.: 84 Cov.: 36 AF XY: 0.0104 AC XY: 7562 AN XY: 724162

African (AFR) AF: 0.00144 AC: 48 AN: 33318

American (AMR) AF: 0.00442 AC: 197 AN: 44540

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 360 AN: 26020

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39620

South Asian (SAS) AF: 0.00264 AC: 226 AN: 85560

European-Finnish (FIN) AF: 0.00789 AC: 410 AN: 51972

Middle Eastern (MID) AF: 0.00837 AC: 35 AN: 4184

European-Non Finnish (NFE) AF: 0.0124 AC: 13735 AN: 1110922

Other (OTH) AF: 0.00813 AC: 488 AN: 60004

GnomAD4 genome AF: 0.00731 AC: 1113 AN: 152214 Hom.: 5 Cov.: 33 AF XY: 0.00720 AC XY: 536 AN XY: 74420

African (AFR) AF: 0.00217 AC: 90 AN: 41550

American (AMR) AF: 0.00759 AC: 116 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00269 AC: 13 AN: 4826

European-Finnish (FIN) AF: 0.00641 AC: 68 AN: 10614

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0114 AC: 777 AN: 67990

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00777 Hom.: 0

Bravo AF: 0.00677

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	CHCHD10-related disorder (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	Lower motor neuron syndrome with late-adult onset;C4014648:Frontotemporal dementia and/or amyotrophic lateral sclerosis 2;C4015513:Autosomal dominant mitochondrial myopathy with exercise intolerance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.4
DANN	Benign	0.93
PhyloP100		-2.3
PromoterAI		-0.066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs111527940; hg19: chr22-24109588; COSMIC: COSV59418272; COSMIC: COSV59418272;