22-23767600-G-T

Variant names:

• chr22-23767600-G-T
• rs567239313
• NM_213720.3:c.42-7C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_213720.3(CHCHD10):​c.42-7C>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 0.00000099 in 1,010,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
• Consequence: CHCHD10 NM_213720.3 splice_region, intron
• Scores: Splicing: ADA: 0.0002020
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.957
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD10	NM_213720.3	c.42-7C>A		splice_region_variant, intron_variant	Intron 1 of 3	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2	c.42-7C>A		splice_region_variant, intron_variant	Intron 1 of 3		NP_001288268.1
CHCHD10	NR_125755.2	n.140-60C>A		intron_variant	Intron 1 of 3
CHCHD10	NR_125756.2	n.139+234C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3	c.42-7C>A		splice_region_variant, intron_variant	Intron 1 of 3	1	NM_213720.3	ENSP00000418428.3
CHCHD10	ENST00000401675.7	c.42-7C>A		splice_region_variant, intron_variant	Intron 1 of 3	5		ENSP00000384973.3
CHCHD10	ENST00000520222.1	c.41+234C>A		intron_variant	Intron 1 of 2	3		ENSP00000430042.1
CHCHD10	ENST00000517886.1	n.42-60C>A		intron_variant	Intron 1 of 3	3		ENSP00000429976.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.90e-7 AC: 1 AN: 1010360 Hom.: 0 Cov.: 14 AF XY: 0.00000202 AC XY: 1 AN XY: 495120

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

African (AFR) AF: 0.00 AC: 0 AN: 19604

American (AMR) AF: 0.00 AC: 0 AN: 9444

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15110

East Asian (EAS) AF: 0.00 AC: 0 AN: 26674

South Asian (SAS) AF: 0.00 AC: 0 AN: 46376

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2966

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 817500

Other (OTH) AF: 0.00 AC: 0 AN: 42866

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.75
PhyloP100		-0.96
PromoterAI		-0.049	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.040
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: rs567239313; hg19: chr22-24109787;