rs141526972

Positions:

• chr22-23767827-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_213720.3(CHCHD10):​c.41+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00214 in 1,541,748 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0022 (8 hom.)
• Consequence: CHCHD10 NM_213720.3 splice_region, intron
• Scores: Splicing: ADA: 0.0001517
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.12

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 22-23767827-C-T is Benign according to our data. Variant chr22-23767827-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 473428.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23767827-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00141 (215/152170) while in subpopulation NFE AF= 0.00279 (190/67998). AF 95% confidence interval is 0.00247. There are 0 homozygotes in gnomad4. There are 84 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 215 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHCHD10	NM_213720.3	c.41+7G>A		splice_region_variant, intron_variant		ENST00000484558.3
CHCHD10	NM_001301339.2	c.41+7G>A		splice_region_variant, intron_variant
CHCHD10	NR_125755.2	n.139+7G>A		splice_region_variant, intron_variant, non_coding_transcript_variant
CHCHD10	NR_125756.2	n.139+7G>A		splice_region_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD10	ENST00000484558.3	c.41+7G>A		splice_region_variant, intron_variant		1	NM_213720.3	P1
CHCHD10	ENST00000401675.7	c.41+7G>A		splice_region_variant, intron_variant		5
CHCHD10	ENST00000520222.1	c.41+7G>A		splice_region_variant, intron_variant		3
CHCHD10	ENST00000517886.1	c.41+7G>A		splice_region_variant, intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 215 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00103 AC: 170 AN: 164424 Hom.: 1 AF XY: 0.00102 AC XY: 95 AN XY: 92784

Gnomad AFR exome AF: 0.000521

Gnomad AMR exome AF: 0.000424

Gnomad ASJ exome AF: 0.00143

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000568

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.00270

GnomAD4 exome AF: 0.00223 AC: 3092 AN: 1389578 Hom.: 8 Cov.: 30 AF XY: 0.00212 AC XY: 1460 AN XY: 688540

Gnomad4 AFR exome AF: 0.000175

Gnomad4 AMR exome AF: 0.000428

Gnomad4 ASJ exome AF: 0.00156

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000127

Gnomad4 FIN exome AF: 0.000261

Gnomad4 NFE exome AF: 0.00267

Gnomad4 OTH exome AF: 0.00242

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.00113 AC XY: 84 AN XY: 74342

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.00188 Hom.: 2

Bravo AF: 0.00122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	CHCHD10: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

CHCHD10-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 05, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.76
DANN	Benign	0.94

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00015
dbscSNV1_RF	Benign	0.0040
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

Publications

LitVar

Other links and lift over

dbSNP: rs141526972; hg19: chr22-24110014;