22-23766134-A-T

Position:

• chr22-23766134-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_213720.3(CHCHD10):​c.403T>A​(p.Tyr135Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. Y135H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHCHD10 NM_213720.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.715

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.025224864).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHCHD10	NM_213720.3	c.403T>A	p.Tyr135Asn	missense_variant	3/4	ENST00000484558.3
CHCHD10	NM_001301339.2	c.424T>A	p.Tyr142Asn	missense_variant	3/4
CHCHD10	NR_125755.2	n.448T>A		non_coding_transcript_exon_variant	3/4
CHCHD10	NR_125756.2	n.281T>A		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHCHD10	ENST00000484558.3	c.403T>A	p.Tyr135Asn	missense_variant	3/4	1	NM_213720.3	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	17
DANN	Benign	0.86
DEOGEN2	Benign	0.0073	T;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.072	T;T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.025	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	.;N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	3.3	N;N
REVEL	Benign	0.048
Sift	Benign	0.55	T;T
Sift4G	Benign	0.38	T;T
Polyphen		0.0	.;B
Vest4		0.12
MutPred		0.36		.;Gain of disorder (P = 0.0205);
MVP		0.048
MPC		0.82
ClinPred		0.38	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.052
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr22-24108321;