rs17849501

Positions:

• chr1-183573188-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000433.4(NCF2):​c.606G>A​(p.Ala202=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,613,450 control chromosomes in the GnomAD database, including 1,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (132 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1674 hom.)
• Consequence: NCF2 NM_000433.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.21

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-183573188-C-T is Benign according to our data. Variant chr1-183573188-C-T is described in ClinVar as [Benign]. Clinvar id is 197668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183573188-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	NM_000433.4	c.606G>A	p.Ala202=	synonymous_variant	5/15	ENST00000367535.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367535.8	c.606G>A	p.Ala202=	synonymous_variant	5/15	1	NM_000433.4	P1

Frequencies

GnomAD3 genomes AF: 0.0353 AC: 5373 AN: 152158 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.00994

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.0387

GnomAD3 exomes AF: 0.0343 AC: 8631 AN: 251482 Hom.: 203 AF XY: 0.0351 AC XY: 4769 AN XY: 135910

Gnomad AFR exome AF: 0.00867

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.0594

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0142

Gnomad FIN exome AF: 0.0361

Gnomad NFE exome AF: 0.0486

Gnomad OTH exome AF: 0.0428

GnomAD4 exome AF: 0.0451 AC: 65910 AN: 1461174 Hom.: 1674 Cov.: 31 AF XY: 0.0443 AC XY: 32225 AN XY: 726958

Gnomad4 AFR exome AF: 0.00848

Gnomad4 AMR exome AF: 0.0276

Gnomad4 ASJ exome AF: 0.0598

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0157

Gnomad4 FIN exome AF: 0.0366

Gnomad4 NFE exome AF: 0.0510

Gnomad4 OTH exome AF: 0.0446

GnomAD4 genome AF: 0.0353 AC: 5369 AN: 152276 Hom.: 132 Cov.: 32 AF XY: 0.0346 AC XY: 2579 AN XY: 74458

Gnomad4 AFR AF: 0.00991

Gnomad4 AMR AF: 0.0396

Gnomad4 ASJ AF: 0.0663

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0124

Gnomad4 FIN AF: 0.0435

Gnomad4 NFE AF: 0.0501

Gnomad4 OTH AF: 0.0383

Alfa AF: 0.0479 Hom.: 350

Bravo AF: 0.0352

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0496

EpiControl AF: 0.0495

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 24163247) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.1
DANN	Benign	0.84

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: rs17849501; hg19: chr1-183542323; COSMIC: COSV62317321; COSMIC: COSV62317321;