rs816411

Variant names:

• chr7-56103796-C-T
• rs816411
• NM_016139.4:c.300+430G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016139.4(CHCHD2):​c.300+430G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 152,096 control chromosomes in the GnomAD database, including 21,697 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.53 (21697 hom., cov: 33)
• Consequence: CHCHD2 NM_016139.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0400
• Publications: 16 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.608 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHCHD2	NM_016139.4	c.300+430G>A		intron_variant	Intron 2 of 3	ENST00000395422.4	NP_057223.1
CHCHD2	NM_001320327.2	c.300+430G>A		intron_variant	Intron 2 of 3		NP_001307256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHCHD2	ENST00000395422.4	c.300+430G>A		intron_variant	Intron 2 of 3	1	NM_016139.4	ENSP00000378812.3
CHCHD2	ENST00000473095.1	n.318+430G>A		intron_variant	Intron 2 of 2	1
CHCHD2	ENST00000716930.1	c.300+430G>A		intron_variant	Intron 2 of 2			ENSP00000520614.1

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80547 AN: 151978 Hom.: 21686 Cov.: 33

Gnomad AFR AF: 0.614

Gnomad AMI AF: 0.567

Gnomad AMR AF: 0.513

Gnomad ASJ AF: 0.567

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.531

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.530 AC: 80605 AN: 152096 Hom.: 21697 Cov.: 33 AF XY: 0.525 AC XY: 38981 AN XY: 74316

African (AFR) AF: 0.614 AC: 25467 AN: 41482

American (AMR) AF: 0.513 AC: 7832 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.567 AC: 1967 AN: 3470

East Asian (EAS) AF: 0.336 AC: 1736 AN: 5172

South Asian (SAS) AF: 0.539 AC: 2594 AN: 4816

European-Finnish (FIN) AF: 0.436 AC: 4605 AN: 10570

Middle Eastern (MID) AF: 0.612 AC: 180 AN: 294

European-Non Finnish (NFE) AF: 0.509 AC: 34592 AN: 68006

Other (OTH) AF: 0.529 AC: 1116 AN: 2110

Alfa AF: 0.523 Hom.: 34775

Bravo AF: 0.543

Asia WGS AF: 0.456 AC: 1586 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.9
DANN	Benign	0.53
PhyloP100		0.040
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs816411; hg19: chr7-56171489;