7-56104067-A-C

Position:

• chr7-56104067-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016139.4(CHCHD2):​c.300+159T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 152,232 control chromosomes in the GnomAD database, including 2,760 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.18 (2760 hom., cov: 34)
• Consequence: CHCHD2 NM_016139.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.483

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 7-56104067-A-C is Benign according to our data. Variant chr7-56104067-A-C is described in ClinVar as [Benign]. Clinvar id is 1180406.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.225 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD2	NM_016139.4	c.300+159T>G		intron_variant		ENST00000395422.4	NP_057223.1
CHCHD2	NM_001320327.2	c.300+159T>G		intron_variant			NP_001307256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHCHD2	ENST00000395422.4	c.300+159T>G		intron_variant		1	NM_016139.4	ENSP00000378812.3
CHCHD2	ENST00000473095.1	n.318+159T>G		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 28057 AN: 152114 Hom.: 2752 Cov.: 34

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.132

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0116

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.172

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.158

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

GnomAD4 genome AF: 0.185 AC: 28089 AN: 152232 Hom.: 2760 Cov.: 34 AF XY: 0.182 AC XY: 13538 AN XY: 74438

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.132

Gnomad4 ASJ AF: 0.160

Gnomad4 EAS AF: 0.0116

Gnomad4 SAS AF: 0.105

Gnomad4 FIN AF: 0.186

Gnomad4 NFE AF: 0.189

Gnomad4 OTH AF: 0.156

Alfa AF: 0.167 Hom.: 2138

Bravo AF: 0.181

Asia WGS AF: 0.0740 AC: 259 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.1
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs6593298; hg19: chr7-56171760;