7-56101726-C-T

Position:

• chr7-56101726-C-T

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.*125G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.837 in 152,192 control chromosomes in the GnomAD database, including 53,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.84 (53799 hom., cov: 32)
  • Exomes 𝑓: 0.79 (227663 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHCHD2 NM_016139.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0150

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-56101726-C-T is Benign according to our data. Variant chr7-56101726-C-T is described in ClinVar as [Benign]. Clinvar id is 1288844.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.947 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHCHD2	NM_016139.4	c.*125G>A		3_prime_UTR_variant	4/4	ENST00000395422.4	NP_057223.1
CHCHD2	NM_001320327.2	c.*78G>A		3_prime_UTR_variant	4/4		NP_001307256.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHCHD2	ENST00000395422	c.*125G>A		3_prime_UTR_variant	4/4	1	NM_016139.4	ENSP00000378812.3

Frequencies

GnomAD3 genomes AF: 0.837 AC: 127305 AN: 152074 Hom.: 53745 Cov.: 32

Gnomad AFR AF: 0.955

Gnomad AMI AF: 0.780

Gnomad AMR AF: 0.768

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.943

Gnomad SAS AF: 0.773

Gnomad FIN AF: 0.815

Gnomad MID AF: 0.788

Gnomad NFE AF: 0.786

Gnomad OTH AF: 0.802

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.793 AC: 571700 AN: 721042 Hom.: 227663 Cov.: 9 AF XY: 0.790 AC XY: 298716 AN XY: 378114

Gnomad4 AFR exome AF: 0.958

Gnomad4 AMR exome AF: 0.759

Gnomad4 ASJ exome AF: 0.778

Gnomad4 EAS exome AF: 0.953

Gnomad4 SAS exome AF: 0.754

Gnomad4 FIN exome AF: 0.811

Gnomad4 NFE exome AF: 0.781

Gnomad4 OTH exome AF: 0.794

GnomAD4 genome AF: 0.837 AC: 127417 AN: 152192 Hom.: 53799 Cov.: 32 AF XY: 0.836 AC XY: 62205 AN XY: 74396

Gnomad4 AFR AF: 0.955

Gnomad4 AMR AF: 0.768

Gnomad4 ASJ AF: 0.775

Gnomad4 EAS AF: 0.943

Gnomad4 SAS AF: 0.773

Gnomad4 FIN AF: 0.815

Gnomad4 NFE AF: 0.786

Gnomad4 OTH AF: 0.801

Alfa AF: 0.814 Hom.: 6290

Bravo AF: 0.840

Asia WGS AF: 0.833 AC: 2899 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	Mar 28, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.64

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: rs8406; hg19: chr7-56169419;