1-183565800-C-T

Position:

• chr1-183565800-C-T

Variant summary

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

The NM_000433.4(NCF2):​c.925-21G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.482 in 1,612,180 control chromosomes in the GnomAD database, including 189,860 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16111 hom., cov: 31)
  • Exomes 𝑓: 0.48 (173749 hom.)
• Consequence: NCF2 NM_000433.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.91

Genes affected

NCF2 (HGNC:7661): (neutrophil cytosolic factor 2) This gene encodes neutrophil cytosolic factor 2, the 67-kilodalton cytosolic subunit of the multi-protein NADPH oxidase complex found in neutrophils. This oxidase produces a burst of superoxide which is delivered to the lumen of the neutrophil phagosome. Mutations in this gene, as well as in other NADPH oxidase subunits, can result in chronic granulomatous disease, a disease that causes recurrent infections by catalase-positive organisms. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2010]

SMG7 (HGNC:16792): (SMG7 nonsense mediated mRNA decay factor) This gene encodes a protein that is essential for nonsense-mediated mRNA decay (NMD); a process whereby transcripts with premature termination codons are targeted for rapid degradation by a mRNA decay complex. The mRNA decay complex consists, in part, of this protein along with proteins SMG5 and UPF1. The N-terminal domain of this protein is thought to mediate its association with SMG5 or UPF1 while the C-terminal domain interacts with the mRNA decay complex. This protein may therefore couple changes in UPF1 phosphorylation state to the degradation of NMD-candidate transcripts. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-183565800-C-T is Benign according to our data. Variant chr1-183565800-C-T is described in ClinVar as [Benign]. Clinvar id is 1235081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183565800-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.597 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCF2	NM_000433.4	c.925-21G>A		intron_variant		ENST00000367535.8	NP_000424.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCF2	ENST00000367535.8	c.925-21G>A		intron_variant		1	NM_000433.4	ENSP00000356505	P1

Frequencies

GnomAD3 genomes AF: 0.455 AC: 69056 AN: 151722 Hom.: 16095 Cov.: 31

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.615

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.474

Gnomad OTH AF: 0.461

GnomAD3 exomes AF: 0.493 AC: 123744 AN: 251004 Hom.: 31529 AF XY: 0.487 AC XY: 66061 AN XY: 135664

Gnomad AFR exome AF: 0.354

Gnomad AMR exome AF: 0.646

Gnomad ASJ exome AF: 0.392

Gnomad EAS exome AF: 0.610

Gnomad SAS exome AF: 0.466

Gnomad FIN exome AF: 0.487

Gnomad NFE exome AF: 0.467

Gnomad OTH exome AF: 0.460

GnomAD4 exome AF: 0.485 AC: 707804 AN: 1460340 Hom.: 173749 Cov.: 34 AF XY: 0.482 AC XY: 350194 AN XY: 726564

Gnomad4 AFR exome AF: 0.348

Gnomad4 AMR exome AF: 0.640

Gnomad4 ASJ exome AF: 0.393

Gnomad4 EAS exome AF: 0.625

Gnomad4 SAS exome AF: 0.466

Gnomad4 FIN exome AF: 0.480

Gnomad4 NFE exome AF: 0.483

Gnomad4 OTH exome AF: 0.472

GnomAD4 genome AF: 0.455 AC: 69094 AN: 151840 Hom.: 16111 Cov.: 31 AF XY: 0.458 AC XY: 33986 AN XY: 74194

Gnomad4 AFR AF: 0.360

Gnomad4 AMR AF: 0.560

Gnomad4 ASJ AF: 0.396

Gnomad4 EAS AF: 0.615

Gnomad4 SAS AF: 0.468

Gnomad4 FIN AF: 0.481

Gnomad4 NFE AF: 0.474

Gnomad4 OTH AF: 0.462

Alfa AF: 0.463 Hom.: 9395

Bravo AF: 0.460

Asia WGS AF: 0.542 AC: 1881 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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	Aug 08, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 82% of patients studied by a panel of primary immunodeficiencies. Number of patients: 78. Only high quality variants are reported. -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.014
DANN	Benign	0.55

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: rs2296164; hg19: chr1-183534935; COSMIC: COSV62315476; COSMIC: COSV62315476;