rs864309650

Positions:

• chr7-56104344-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The NM_016139.4(CHCHD2):​c.182C>T​(p.Thr61Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHCHD2 NM_016139.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.49

Genes affected

CHCHD2 (HGNC:21645): (coiled-coil-helix-coiled-coil-helix domain containing 2) The protein encoded by this gene belongs to a class of eukaryotic CX(9)C proteins characterized by four cysteine residues spaced ten amino acids apart from one another. These residues form disulfide linkages that define a CHCH fold. In response to stress, the protein translocates from the mitochondrial intermembrane space to the nucleus where it binds to a highly conserved 13 nucleotide oxygen responsive element in the promoter of cytochrome oxidase 4I2, a subunit of the terminal enzyme of the electron transport chain. In concert with recombination signal sequence-binding protein J, binding of this protein activates the oxygen responsive element at four percent oxygen. In addition, it has been shown that this protein is a negative regulator of mitochondria-mediated apoptosis. In response to apoptotic stimuli, mitochondrial levels of this protein decrease, allowing BCL2-associated X protein to oligomerize and activate the caspase cascade. Pseudogenes of this gene are found on multiple chromosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

CHCHD2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-56104344-G-A is Pathogenic according to our data. Variant chr7-56104344-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 218882.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD2	NM_016139.4	c.182C>T	p.Thr61Ile	missense_variant	2/4	ENST00000395422.4	NP_057223.1
CHCHD2	NM_001320327.2	c.182C>T	p.Thr61Ile	missense_variant	2/4		NP_001307256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHCHD2	ENST00000395422.4	c.182C>T	p.Thr61Ile	missense_variant	2/4	1	NM_016139.4	ENSP00000378812.3
CHCHD2	ENST00000473095.1	n.200C>T		non_coding_transcript_exon_variant	2/3	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson disease 22, autosomal dominant Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2015

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 17, 2023

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CHCHD2 function (PMID: 28432706, 30530185, 31600778, 32068847). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 218882). This missense change has been observed in individual(s) with autosomal dominant Parkinson disease (PMID: 25662902, 35402650). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 61 of the CHCHD2 protein (p.Thr61Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.18	T
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.32		Loss of glycosylation at T61 (P = 0.003);
MVP		0.77
MPC		0.96
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.59
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs864309650; hg19: chr7-56172037;