1-183573252-T-C

Variant names:

• chr1-183573252-T-C
• rs2274064
• NM_000433.4:c.542A>G

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.542A>G​(p.Lys181Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,613,334 control chromosomes in the GnomAD database, including 191,513 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16273 hom., cov: 32)
  • Exomes 𝑓: 0.49 (175240 hom.)
• Consequence: NCF2 NM_000433.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 0.615
• Publications: 60 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=3.207979E-5).
• BP6: Variant 1-183573252-T-C is Benign according to our data. Variant chr1-183573252-T-C is described in ClinVar as Benign. ClinVar VariationId is 256116.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF2	NM_000433.4	c.542A>G	p.Lys181Arg	missense_variant	Exon 5 of 15	ENST00000367535.8	NP_000424.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCF2	ENST00000367535.8	c.542A>G	p.Lys181Arg	missense_variant	Exon 5 of 15	1	NM_000433.4	ENSP00000356505.4

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69469 AN: 151888 Hom.: 16259 Cov.: 32

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.566

Gnomad AMR AF: 0.560

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.513

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.344

Gnomad NFE AF: 0.473

Gnomad OTH AF: 0.458

GnomAD2 exomes AF: 0.499 AC: 125404 AN: 251436 AF XY: 0.494

Gnomad AFR exome AF: 0.359

Gnomad AMR exome AF: 0.645

Gnomad ASJ exome AF: 0.391

Gnomad EAS exome AF: 0.623

Gnomad FIN exome AF: 0.486

Gnomad NFE exome AF: 0.466

Gnomad OTH exome AF: 0.461

GnomAD4 exome AF: 0.486 AC: 710885 AN: 1461330 Hom.: 175240 Cov.: 52 AF XY: 0.485 AC XY: 352498 AN XY: 727014

African (AFR) AF: 0.352 AC: 11788 AN: 33472

American (AMR) AF: 0.639 AC: 28588 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 10246 AN: 26130

East Asian (EAS) AF: 0.629 AC: 24963 AN: 39698

South Asian (SAS) AF: 0.504 AC: 43457 AN: 86246

European-Finnish (FIN) AF: 0.478 AC: 25527 AN: 53392

Middle Eastern (MID) AF: 0.351 AC: 2022 AN: 5766

European-Non Finnish (NFE) AF: 0.482 AC: 535725 AN: 1111526

Other (OTH) AF: 0.473 AC: 28569 AN: 60376

GnomAD4 genome AF: 0.457 AC: 69503 AN: 152004 Hom.: 16273 Cov.: 32 AF XY: 0.461 AC XY: 34232 AN XY: 74296

African (AFR) AF: 0.364 AC: 15104 AN: 41452

American (AMR) AF: 0.561 AC: 8566 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1369 AN: 3466

East Asian (EAS) AF: 0.620 AC: 3191 AN: 5146

South Asian (SAS) AF: 0.511 AC: 2458 AN: 4814

European-Finnish (FIN) AF: 0.480 AC: 5076 AN: 10576

Middle Eastern (MID) AF: 0.349 AC: 102 AN: 292

European-Non Finnish (NFE) AF: 0.473 AC: 32152 AN: 67970

Other (OTH) AF: 0.459 AC: 969 AN: 2112

Alfa AF: 0.468 Hom.: 83649

Bravo AF: 0.461

TwinsUK AF: 0.505 AC: 1872

ALSPAC AF: 0.491 AC: 1891

ESP6500AA AF: 0.359 AC: 1581

ESP6500EA AF: 0.467 AC: 4012

ExAC AF: 0.489 AC: 59412

Asia WGS AF: 0.560 AC: 1943 AN: 3478

EpiCase AF: 0.452

EpiControl AF: 0.460

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 Benign:3

Jan 13, 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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2 Other:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	17
DANN	Benign	0.69
DEOGEN2	Benign	0.040	.;T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.15	T;.;T
MetaRNN	Benign	0.000032	T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	.;N;N
PhyloP100		0.61
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.18	N;N;N
REVEL	Benign	0.084
Sift	Benign	0.91	T;T;T
Sift4G	Benign	0.86	T;T;T
Polyphen		0.0	.;B;B
Vest4		0.050
MPC		0.25
ClinPred		0.0010	T
GERP RS		1.3
Varity_R		0.12
gMVP		0.34
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: rs2274064; hg19: chr1-183542387; COSMIC: COSV62314890; COSMIC: COSV62314890;