NM_213720.3:c.43C>A

Variant names:

• chr22-23767592-G-T
• rs730880032
• NM_213720.3:c.43C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 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).

• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2360399).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD10	NM_213720.3	c.43C>A	p.Arg15Ser	missense_variant, splice_region_variant	Exon 2 of 4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2	c.43C>A	p.Arg15Ser	missense_variant, splice_region_variant	Exon 2 of 4		NP_001288268.1
CHCHD10	NR_125755.2	n.140-52C>A		intron_variant	Intron 1 of 3
CHCHD10	NR_125756.2	n.139+242C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3	c.43C>A	p.Arg15Ser	missense_variant, splice_region_variant	Exon 2 of 4	1	NM_213720.3	ENSP00000418428.3
CHCHD10	ENST00000401675.7	c.43C>A	p.Arg15Ser	missense_variant, splice_region_variant	Exon 2 of 4	5		ENSP00000384973.3
CHCHD10	ENST00000520222.1	c.41+242C>A		intron_variant	Intron 1 of 2	3		ENSP00000430042.1
CHCHD10	ENST00000517886.1	n.42-52C>A		intron_variant	Intron 1 of 3	3		ENSP00000429976.1

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
MutationAssessor	Uncertain	2.3	.;M
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;