rs567239313

Positions:

• chr22-23767600-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000484558.3(CHCHD10):​c.42-7C>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,162,580 control chromosomes in the GnomAD database, including 120 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (49 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (71 hom.)
• Consequence: CHCHD10 ENST00000484558.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002668
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.957

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=-0.83).
• BP6: Variant 22-23767600-G-C is Benign according to our data. Variant chr22-23767600-G-C is described in ClinVar as [Benign]. Clinvar id is 473429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-23767600-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD10	NM_213720.3	c.42-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2	c.42-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001288268.1
CHCHD10	NR_125755.2	n.140-60C>G		intron_variant, non_coding_transcript_variant
CHCHD10	NR_125756.2	n.139+234C>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3	c.42-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_213720.3	ENSP00000418428	P1
CHCHD10	ENST00000401675.7	c.42-7C>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000384973
CHCHD10	ENST00000520222.1	c.41+234C>G		intron_variant		3		ENSP00000430042
CHCHD10	ENST00000517886.1	c.42-60C>G		intron_variant, NMD_transcript_variant		3		ENSP00000429976

Frequencies

GnomAD3 genomes AF: 0.0143 AC: 2176 AN: 152106 Hom.: 49 Cov.: 32

Gnomad AFR AF: 0.0487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.000304 AC: 1 AN: 3292 Hom.: 0 AF XY: 0.000538 AC XY: 1 AN XY: 1860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00194

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00157 AC: 1589 AN: 1010364 Hom.: 71 Cov.: 14 AF XY: 0.00154 AC XY: 762 AN XY: 495120

Gnomad4 AFR exome AF: 0.0537

Gnomad4 AMR exome AF: 0.00381

Gnomad4 ASJ exome AF: 0.00933

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.00448

GnomAD4 genome AF: 0.0143 AC: 2179 AN: 152216 Hom.: 49 Cov.: 32 AF XY: 0.0140 AC XY: 1044 AN XY: 74432

Gnomad4 AFR AF: 0.0487

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.0119 Hom.: 4

Bravo AF: 0.0167

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2020	- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.75
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00027
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.070		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: rs567239313; hg19: chr22-24109787;