NM_000433.4:c.606G>A

Variant names:

• chr1-183573188-C-T
• rs17849501
• NM_000433.4:c.606G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000433.4(NCF2):​c.606G>A​(p.Ala202Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0442 in 1,613,450 control chromosomes in the GnomAD database, including 1,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (132 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1674 hom.)
• Consequence: NCF2 NM_000433.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -1.21
• Publications: 31 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 1-183573188-C-T is Benign according to our data. Variant chr1-183573188-C-T is described in ClinVar as Benign. ClinVar VariationId is 197668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.21 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0506 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCF2	NM_000433.4	c.606G>A	p.Ala202Ala	synonymous_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.606G>A	p.Ala202Ala	synonymous_variant	Exon 5 of 15	1	NM_000433.4	ENSP00000356505.4

Frequencies

GnomAD3 genomes AF: 0.0353 AC: 5373 AN: 152158 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.00994

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0663

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.0387

GnomAD2 exomes AF: 0.0343 AC: 8631 AN: 251482 AF XY: 0.0351

Gnomad AFR exome AF: 0.00867

Gnomad AMR exome AF: 0.0255

Gnomad ASJ exome AF: 0.0594

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0361

Gnomad NFE exome AF: 0.0486

Gnomad OTH exome AF: 0.0428

GnomAD4 exome AF: 0.0451 AC: 65910 AN: 1461174 Hom.: 1674 Cov.: 31 AF XY: 0.0443 AC XY: 32225 AN XY: 726958

African (AFR) AF: 0.00848 AC: 284 AN: 33474

American (AMR) AF: 0.0276 AC: 1236 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0598 AC: 1562 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.0157 AC: 1354 AN: 86240

European-Finnish (FIN) AF: 0.0366 AC: 1954 AN: 53402

Middle Eastern (MID) AF: 0.0302 AC: 173 AN: 5726

European-Non Finnish (NFE) AF: 0.0510 AC: 56654 AN: 1111412

Other (OTH) AF: 0.0446 AC: 2692 AN: 60370

GnomAD4 genome AF: 0.0353 AC: 5369 AN: 152276 Hom.: 132 Cov.: 32 AF XY: 0.0346 AC XY: 2579 AN XY: 74458

African (AFR) AF: 0.00991 AC: 412 AN: 41558

American (AMR) AF: 0.0396 AC: 606 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0663 AC: 230 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5170

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4832

European-Finnish (FIN) AF: 0.0435 AC: 462 AN: 10614

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0501 AC: 3408 AN: 68020

Other (OTH) AF: 0.0383 AC: 81 AN: 2114

Alfa AF: 0.0468 Hom.: 475

Bravo AF: 0.0352

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0496

EpiControl AF: 0.0495

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 05, 2015

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: 24163247) -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.1
DANN	Benign	0.84
PhyloP100		-1.2
Mutation Taster		=98/2	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: rs17849501; hg19: chr1-183542323; COSMIC: COSV62317321; COSMIC: COSV62317321;