rs864309650

Variant names:

• chr7-56104344-G-A
• rs864309650
• NM_016139.4:c.182C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV004295206: Experimental studies have shown that this missense change affects CHCHD2 function (PMID:28432706, 30530185, 31600778, 32068847).". Synonymous variant affecting the same amino acid position (i.e. T61T) has been classified as Likely benign.

• 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
• Publications: 44 publications found

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 Gene-Disease associations (from GenCC):

• Parkinson disease 22, autosomal dominant

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004295206: Experimental studies have shown that this missense change affects CHCHD2 function (PMID: 28432706, 30530185, 31600778, 32068847).
• 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 VariationId is 218882.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016139.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD2	NM_016139.4	MANE Select	c.182C>T	p.Thr61Ile	missense	Exon 2 of 4	NP_057223.1	Q9Y6H1
	CHCHD2	NM_001320327.2		c.182C>T	p.Thr61Ile	missense	Exon 2 of 4	NP_001307256.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHCHD2	ENST00000395422.4	TSL:1 MANE Select	c.182C>T	p.Thr61Ile	missense	Exon 2 of 4	ENSP00000378812.3	Q9Y6H1
	CHCHD2	ENST00000473095.1	TSL:1	n.200C>T		non_coding_transcript_exon	Exon 2 of 3
	CHCHD2	ENST00000962119.1		c.182C>T	p.Thr61Ile	missense	Exon 2 of 4	ENSP00000632178.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Parkinson disease 22, autosomal dominant (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		5.5
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
Mutation Taster		=23/77	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs864309650; hg19: chr7-56172037;