1-183563302-G-A

Variant names:

• chr1-183563302-G-A
• rs13306575
• NM_000433.4:c.1183C>T

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.1183C>T​(p.Arg395Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,614,072 control chromosomes in the GnomAD database, including 361 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R395Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0057 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0042 (337 hom.)
• Consequence: NCF2 NM_000433.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 1.76
• Publications: 40 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 (MetaRNN=0.0075665414).
• BP6: Variant 1-183563302-G-A is Benign according to our data. Variant chr1-183563302-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0931 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000433.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF2	NM_000433.4	MANE Select	c.1183C>T	p.Arg395Trp	missense	Exon 13 of 15	NP_000424.2	P19878-1
	NCF2	NM_001127651.3		c.1183C>T	p.Arg395Trp	missense	Exon 14 of 16	NP_001121123.1	P19878-1
	NCF2	NM_001410895.1		c.1075C>T	p.Arg359Trp	missense	Exon 13 of 15	NP_001397824.1	A0A8V8TMB9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF2	ENST00000367535.8	TSL:1 MANE Select	c.1183C>T	p.Arg395Trp	missense	Exon 13 of 15	ENSP00000356505.4	P19878-1
	NCF2	ENST00000367536.5	TSL:1	c.1183C>T	p.Arg395Trp	missense	Exon 14 of 16	ENSP00000356506.1	P19878-1
	NCF2	ENST00000946295.1		c.1183C>T	p.Arg395Trp	missense	Exon 13 of 16	ENSP00000616354.1

Frequencies

GnomAD3 genomes AF: 0.00565 AC: 860 AN: 152164 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0331

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0455

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00673

GnomAD2 exomes AF: 0.0186 AC: 4665 AN: 251332 AF XY: 0.0143

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0449

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000703

Gnomad OTH exome AF: 0.00783

GnomAD4 exome AF: 0.00418 AC: 6113 AN: 1461790 Hom.: 337 Cov.: 32 AF XY: 0.00356 AC XY: 2592 AN XY: 727194

African (AFR) AF: 0.00116 AC: 39 AN: 33478

American (AMR) AF: 0.0955 AC: 4271 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0343 AC: 1362 AN: 39696

South Asian (SAS) AF: 0.00126 AC: 109 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1111992

Other (OTH) AF: 0.00462 AC: 279 AN: 60394

GnomAD4 genome AF: 0.00565 AC: 861 AN: 152282 Hom.: 24 Cov.: 32 AF XY: 0.00611 AC XY: 455 AN XY: 74452

African (AFR) AF: 0.00195 AC: 81 AN: 41562

American (AMR) AF: 0.0330 AC: 505 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0460 AC: 238 AN: 5174

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.00666 AC: 14 AN: 2102

Alfa AF: 0.00408 Hom.: 126

Bravo AF: 0.0107

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0151 AC: 1834

Asia WGS AF: 0.0230 AC: 79 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	4	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (5)
-	-	4	not specified (4)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.31
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		1.8
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.1	D
REVEL	Benign	0.22
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.99	D
Vest4		0.55
MPC		1.0
ClinPred		0.059	T
GERP RS		4.8
Varity_R		0.66
gMVP		0.61
Mutation Taster		=92/8	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: rs13306575; hg19: chr1-183532437; COSMIC: COSV62316815;