rs2274065

Positions:

• chr1-183590569-A-C

Variant summary

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

The ENST00000367536.5(NCF2):​c.-30-210T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 585,042 control chromosomes in the GnomAD database, including 7,557 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (4548 hom., cov: 32)
  • Exomes 𝑓: 0.094 (3009 hom.)
• Consequence: NCF2 ENST00000367536.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.201

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=-0.83).
• BP6: Variant 1-183590569-A-C is Benign according to our data. Variant chr1-183590569-A-C is described in ClinVar as [Benign]. Clinvar id is 294087.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.431 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	XM_011509581.2	c.-78T>G		5_prime_UTR_variant	1/16
NCF2	NM_001127651.3	c.-30-210T>G		intron_variant
NCF2	NM_001410895.1	c.-30-210T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367536.5	c.-30-210T>G		intron_variant		1		P1
NCF2	ENST00000413720.5	c.-240T>G		5_prime_UTR_variant	1/14	2
NCF2	ENST00000418089.5	c.-240T>G		5_prime_UTR_variant	1/13	2

Frequencies

GnomAD3 genomes AF: 0.188 AC: 28587 AN: 151664 Hom.: 4540 Cov.: 32

Gnomad AFR AF: 0.437

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.0761

Gnomad EAS AF: 0.0757

Gnomad SAS AF: 0.0706

Gnomad FIN AF: 0.102

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0741

Gnomad OTH AF: 0.160

GnomAD4 exome AF: 0.0940 AC: 40734 AN: 433260 Hom.: 3009 Cov.: 3 AF XY: 0.0900 AC XY: 20796 AN XY: 231168

Gnomad4 AFR exome AF: 0.432

Gnomad4 AMR exome AF: 0.210

Gnomad4 ASJ exome AF: 0.0800

Gnomad4 EAS exome AF: 0.0847

Gnomad4 SAS exome AF: 0.0720

Gnomad4 FIN exome AF: 0.0938

Gnomad4 NFE exome AF: 0.0718

Gnomad4 OTH exome AF: 0.110

GnomAD4 genome AF: 0.189 AC: 28642 AN: 151782 Hom.: 4548 Cov.: 32 AF XY: 0.187 AC XY: 13879 AN XY: 74134

Gnomad4 AFR AF: 0.437

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.0761

Gnomad4 EAS AF: 0.0757

Gnomad4 SAS AF: 0.0709

Gnomad4 FIN AF: 0.102

Gnomad4 NFE AF: 0.0742

Gnomad4 OTH AF: 0.158

Alfa AF: 0.0917 Hom.: 1432

Bravo AF: 0.208

Asia WGS AF: 0.0940 AC: 327 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 11, 2018

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.1
DANN	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs2274065; hg19: chr1-183559704;