1-183563445-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000433.4(NCF2):c.1167C>A(p.His389Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0443 in 1,614,162 control chromosomes in the GnomAD database, including 1,811 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H389N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.035 ( 131 hom., cov: 32)

Exomes 𝑓: 0.045 ( 1680 hom. )

Consequence

NCF2
NM_000433.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.71

Publications

63 publications found

Variant links:

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]

NCF2 links:

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

SMG7 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023945272).

BP6

Variant 1-183563445-G-T is Benign according to our data. Variant chr1-183563445-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0509 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF2	NM_000433.4 link	c.1167C>A	p.His389Gln	missense_variant	Exon 12 of 15	ENST00000367535.8	NP_000424.2	P19878-1A0A0S2Z457

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF2	ENST00000367535.8 link	c.1167C>A	p.His389Gln	missense_variant	Exon 12 of 15	1	NM_000433.4	ENSP00000356505.4		P19878-1

Frequencies

GnomAD3 genomes

AF:

0.0352

AC:

5350

AN:

152174

Hom.:

131

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00994

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.0389

Gnomad ASJ

AF:

0.0663

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0126

Gnomad FIN

AF:

0.0434

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0500

Gnomad OTH

AF:

0.0382

GnomAD2 exomes

AF:

0.0344

AC:

8639

AN:

251310

AF XY:

0.0351

show subpopulations

Gnomad AFR exome

AF:

0.00867

Gnomad AMR exome

AF:

0.0254

Gnomad ASJ exome

AF:

0.0594

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0360

Gnomad NFE exome

AF:

0.0488

Gnomad OTH exome

AF:

0.0426

GnomAD4 exome

AF:

0.0453

AC:

66189

AN:

1461870

Hom.:

1680

Cov.:

AF XY:

0.0445

AC XY:

32332

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.00839

AC:

281

AN:

33480

American (AMR)

AF:

0.0274

AC:

1224

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0598

AC:

1563

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39694

South Asian (SAS)

AF:

0.0157

AC:

1352

AN:

86258

European-Finnish (FIN)

AF:

0.0366

AC:

1957

AN:

53414

Middle Eastern (MID)

AF:

0.0283

AC:

163

AN:

5768

European-Non Finnish (NFE)

AF:

0.0512

AC:

56953

AN:

1112008

Other (OTH)

AF:

0.0446

AC:

2695

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

4238

8475

12713

16950

21188

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2102

4204

6306

8408

10510

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0351

AC:

5347

AN:

152292

Hom.:

131

Cov.:

AF XY:

0.0344

AC XY:

2564

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.00991

AC:

412

AN:

41566

American (AMR)

AF:

0.0389

AC:

594

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0663

AC:

230

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5188

South Asian (SAS)

AF:

0.0124

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0434

AC:

460

AN:

10610

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0500

AC:

3403

AN:

68024

Other (OTH)

AF:

0.0378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

277

553

830

1106

1383

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0440

Hom.:

541

Bravo

AF:

0.0350

TwinsUK

AF:

0.0491

AC:

182

ALSPAC

AF:

0.0462

AC:

178

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.0502

AC:

432

ExAC

AF:

0.0343

AC:

4160

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0496

EpiControl

AF:

0.0494

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Dec 03, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26502338, 22203994, 23821607, 25795782, 24163247) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

.;.;T;T;T;T

Eigen

Uncertain

0.29

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.86

D;D;.;D;D;D

MetaRNN

Benign

0.0024

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

.;.;M;M;.;.

PhyloP100

1.7

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.5

N;D;D;D;D;D

REVEL

Benign

0.12

Sift

Benign

0.23

T;T;T;T;D;T

Sift4G

Benign

0.17

T;T;T;T;.;.

Polyphen

0.98

.;.;D;D;.;.

Vest4

0.39

MutPred

0.13

.;.;Gain of MoRF binding (P = 0.0867);Gain of MoRF binding (P = 0.0867);.;.;

MPC

1.0

ClinPred

0.021

GERP RS

1.7

Varity_R

0.49

gMVP

0.35

Mutation Taster

=64/36

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over