chr1-183565800-C-T

Variant names:

• chr1-183565800-C-T
• rs2296164
• NM_000433.4:c.925-21G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 26 publications found

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]

SMG7 Gene-Disease associations (from GenCC):

• autoimmune disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: Illumina

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 1235081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
NCF2	NM_000433.4	c.925-21G>A		intron_variant	Intron 9 of 14	ENST00000367535.8	NP_000424.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF2	ENST00000367535.8	c.925-21G>A		intron_variant	Intron 9 of 14	1	NM_000433.4	ENSP00000356505.4

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

GnomAD2 exomes AF: 0.493 AC: 123744 AN: 251004 AF XY: 0.487

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 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

African (AFR) AF: 0.348 AC: 11645 AN: 33442

American (AMR) AF: 0.640 AC: 28583 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 10267 AN: 26116

East Asian (EAS) AF: 0.625 AC: 24773 AN: 39662

South Asian (SAS) AF: 0.466 AC: 40151 AN: 86216

European-Finnish (FIN) AF: 0.480 AC: 25613 AN: 53406

Middle Eastern (MID) AF: 0.345 AC: 1928 AN: 5588

European-Non Finnish (NFE) AF: 0.483 AC: 536382 AN: 1110906

Other (OTH) AF: 0.472 AC: 28462 AN: 60324

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

African (AFR) AF: 0.360 AC: 14891 AN: 41372

American (AMR) AF: 0.560 AC: 8547 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1375 AN: 3470

East Asian (EAS) AF: 0.615 AC: 3174 AN: 5158

South Asian (SAS) AF: 0.468 AC: 2256 AN: 4816

European-Finnish (FIN) AF: 0.481 AC: 5066 AN: 10534

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.474 AC: 32197 AN: 67930

Other (OTH) AF: 0.462 AC: 971 AN: 2104

Alfa AF: 0.463 Hom.: 12516

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Aug 08, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.014
DANN	Benign	0.55
PhyloP100		-2.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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