22-23767592-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_213720.3(CHCHD10):c.43C>A(p.Arg15Ser) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000933 in 1,071,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as no classification for the single variant (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R15L) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.3e-7 (0 hom.)
• Consequence: CHCHD10 NM_213720.3 missense, splice_region
• Scores: Splicing: ADA: 0.9443
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr22-23767591-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 180220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2360399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHCHD10	NM_213720.3	c.43C>A	p.Arg15Ser	missense_variant, splice_region_variant	2/4	ENST00000484558.3
CHCHD10	NM_001301339.2	c.43C>A	p.Arg15Ser	missense_variant, splice_region_variant	2/4
CHCHD10	NR_125755.2	n.140-52C>A		intron_variant, non_coding_transcript_variant
CHCHD10	NR_125756.2	n.139+242C>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD10	ENST00000484558.3	c.43C>A	p.Arg15Ser	missense_variant, splice_region_variant	2/4	1	NM_213720.3	P1
CHCHD10	ENST00000401675.7	c.43C>A	p.Arg15Ser	missense_variant, splice_region_variant	2/4	5
CHCHD10	ENST00000520222.1	c.41+242C>A		intron_variant		3
CHCHD10	ENST00000517886.1	c.42-52C>A		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.33e-7 AC: 1 AN: 1071338 Hom.: 0 Cov.: 16 AF XY: 0.00000191 AC XY: 1 AN XY: 522302

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000114

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.067	T
BayesDel_noAF	Benign	-0.33
Cadd	Pathogenic	33
Dann	Uncertain	0.98
DEOGEN2	Benign	0.020	T;T
Eigen	Benign	0.053
Eigen_PC	Benign	0.040
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.56	T;T
M_CAP	Pathogenic	0.36	D
MetaRNN	Benign	0.24	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.27
Sift	Benign	0.11	T;T
Sift4G	Benign	0.10	T;T
Polyphen		0.99	.;D
Vest4		0.28
MutPred		0.32		Gain of phosphorylation at R15 (P = 0.0013);Gain of phosphorylation at R15 (P = 0.0013);
MVP		0.29
MPC		0.57
ClinPred		0.74	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.1
Varity_R		0.28
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.94
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.79		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730880032; hg19: chr22-24109779;