rs12753665

Positions:

• chr1-183576926-G-A
• chr1-183576926-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000433.4(NCF2):​c.366+673C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.348 in 151,988 control chromosomes in the GnomAD database, including 9,335 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (9335 hom., cov: 33)
• Consequence: NCF2 NM_000433.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.13

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.53 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	NM_000433.4	c.366+673C>T		intron_variant		ENST00000367535.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367535.8	c.366+673C>T		intron_variant		1	NM_000433.4	P1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52791 AN: 151870 Hom.: 9326 Cov.: 33

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.313

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.399

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.327

Gnomad OTH AF: 0.351

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.348 AC: 52819 AN: 151988 Hom.: 9335 Cov.: 33 AF XY: 0.351 AC XY: 26039 AN XY: 74282

Gnomad4 AFR AF: 0.332

Gnomad4 AMR AF: 0.401

Gnomad4 ASJ AF: 0.313

Gnomad4 EAS AF: 0.547

Gnomad4 SAS AF: 0.397

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.327

Gnomad4 OTH AF: 0.353

Alfa AF: 0.332 Hom.: 9346

Bravo AF: 0.353

Asia WGS AF: 0.498 AC: 1725 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.2
DANN	Benign	0.69

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: rs12753665; hg19: chr1-183546061;