chr22-23766129-A-T

Variant names:

• chr22-23766129-A-T
• rs113677828
• NM_213720.3:c.408T>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.408T>A​(p.His136Gln) variant causes a missense, splice region 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. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 30)
• Consequence: CHCHD10 NM_213720.3 missense, splice_region
• Scores: Splicing: ADA: 0.00008362
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.58

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=0.13556612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD10	NM_213720.3	c.408T>A	p.His136Gln	missense_variant, splice_region_variant	Exon 3 of 4	ENST00000484558.3	NP_998885.1
CHCHD10	NM_001301339.2	c.429T>A	p.His143Gln	missense_variant, splice_region_variant	Exon 3 of 4		NP_001288268.1
CHCHD10	NR_125755.2	n.453T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 3 of 4
CHCHD10	NR_125756.2	n.286T>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD10	ENST00000484558.3	c.408T>A	p.His136Gln	missense_variant, splice_region_variant	Exon 3 of 4	1	NM_213720.3	ENSP00000418428.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 65

GnomAD4 genome Cov.: 30

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.2
DANN	Benign	0.91
DEOGEN2	Benign	0.098	T;T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.50	T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	.;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.065
Sift	Benign	0.030	D;D
Sift4G	Benign	0.20	T;T
Polyphen		0.65	.;P
Vest4		0.27
MutPred		0.25		.;Gain of disorder (P = 0.0303);
MVP		0.076
MPC		0.54
ClinPred		0.62	D
GERP RS		-4.8
Varity_R		0.13
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000084
dbscSNV1_RF	Benign	0.082
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: rs113677828; hg19: chr22-24108316;