7-56101980-G-GT

Position:

• chr7-56101980-G-GT

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_016139.4(CHCHD2):​c.446-120dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00493 in 939,566 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0044 (4 hom.)
• Consequence: CHCHD2 NM_016139.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.824

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP6: Variant 7-56101980-G-GT is Benign according to our data. Variant chr7-56101980-G-GT is described in ClinVar as [Likely_benign]. Clinvar id is 1300703.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00794 (1196/150662) while in subpopulation AFR AF= 0.0263 (1078/41034). AF 95% confidence interval is 0.025. There are 17 homozygotes in gnomad4. There are 577 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1196 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD2	NM_016139.4	c.446-120dupA		intron_variant		ENST00000395422.4	NP_057223.1
CHCHD2	NM_001320327.2	c.450-120dupA		intron_variant			NP_001307256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHCHD2	ENST00000395422.4	c.446-120dupA		intron_variant		1	NM_016139.4	ENSP00000378812.3

Frequencies

GnomAD3 genomes AF: 0.00786 AC: 1184 AN: 150552 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00320

Gnomad ASJ AF: 0.000290

Gnomad EAS AF: 0.000388

Gnomad SAS AF: 0.00379

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000577

Gnomad OTH AF: 0.00533

GnomAD4 exome AF: 0.00435 AC: 3433 AN: 788904 Hom.: 4 AF XY: 0.00429 AC XY: 1770 AN XY: 412680

Gnomad4 AFR exome AF: 0.0270

Gnomad4 AMR exome AF: 0.00576

Gnomad4 ASJ exome AF: 0.00338

Gnomad4 EAS exome AF: 0.00258

Gnomad4 SAS exome AF: 0.00681

Gnomad4 FIN exome AF: 0.00197

Gnomad4 NFE exome AF: 0.00349

Gnomad4 OTH exome AF: 0.00671

GnomAD4 genome AF: 0.00794 AC: 1196 AN: 150662 Hom.: 17 Cov.: 32 AF XY: 0.00784 AC XY: 577 AN XY: 73560

Gnomad4 AFR AF: 0.0263

Gnomad4 AMR AF: 0.00319

Gnomad4 ASJ AF: 0.000290

Gnomad4 EAS AF: 0.000389

Gnomad4 SAS AF: 0.00358

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000577

Gnomad4 OTH AF: 0.00528

Bravo AF: 0.00914

Asia WGS AF: 0.0100 AC: 35 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs112334416; hg19: chr7-56169673;