rs781304084

chr22-23767445-C-Gchr22-23767445-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_213720.3(CHCHD10):c.190G>C(p.Val64Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,451,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V64I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.15

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.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_213720.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21916679).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHCHD10	NM_213720.3	c.190G>C	p.Val64Leu	missense_variant	2/4	ENST00000484558.3
CHCHD10	NM_001301339.2	c.190G>C	p.Val64Leu	missense_variant	2/4
CHCHD10	NR_125755.2	n.235G>C		non_coding_transcript_exon_variant	2/4
CHCHD10	NR_125756.2	n.139+389G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD10	ENST00000484558.3	c.190G>C	p.Val64Leu	missense_variant	2/4	1	NM_213720.3	P1
CHCHD10	ENST00000401675.7	c.190G>C	p.Val64Leu	missense_variant	2/4	5
CHCHD10	ENST00000520222.1	c.41+389G>C		intron_variant		3
CHCHD10	ENST00000517886.1	c.137G>C	p.Arg46Pro	missense_variant, NMD_transcript_variant	2/4	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1451944 Hom.: 0 Cov.: 36 AF XY: 0.00000277 AC XY: 2 AN XY: 721788

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: 0.0000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000836 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
Cadd	Pathogenic	27
Dann	Benign	0.94
DEOGEN2	Benign	0.043	T;T
Eigen	Benign	0.16
Eigen_PC	Benign	0.035
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	0.94	D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.12
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.99	.;D
Vest4		0.27
MutPred		0.31		Gain of helix (P = 0.062);Gain of helix (P = 0.062);
MVP		0.17
MPC		1.4
ClinPred		0.82	D
GERP RS		2.6
Varity_R		0.17
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs781304084; hg19: chr22-24109632;