rs55761650

Variant names:

• chr1-183560204-G-A
• rs55761650
• NM_000433.4:c.1360C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-183560204-G-A
• chr1-183560204-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000433.4(NCF2):​c.1360C>T​(p.Pro454Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 1,614,138 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (30 hom.)
• Consequence: NCF2 NM_000433.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.0310
• Publications: 13 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=0.004563093).
• BP6: Variant 1-183560204-G-A is Benign according to our data. Variant chr1-183560204-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294076.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0047 (716/152256) while in subpopulation AMR AF = 0.00804 (123/15292). AF 95% confidence interval is 0.00689. There are 7 homozygotes in GnomAd4. There are 303 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

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.1360C>T	p.Pro454Ser	missense	Exon 14 of 15	NP_000424.2	P19878-1
	NCF2	NM_001127651.3		c.1360C>T	p.Pro454Ser	missense	Exon 15 of 16	NP_001121123.1	P19878-1
	NCF2	NM_001410895.1		c.1252C>T	p.Pro418Ser	missense	Exon 14 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.1360C>T	p.Pro454Ser	missense	Exon 14 of 15	ENSP00000356505.4	P19878-1
	NCF2	ENST00000367536.5	TSL:1	c.1360C>T	p.Pro454Ser	missense	Exon 15 of 16	ENSP00000356506.1	P19878-1
	NCF2	ENST00000946295.1		c.1360C>T	p.Pro454Ser	missense	Exon 14 of 16	ENSP00000616354.1

Frequencies

GnomAD3 genomes AF: 0.00471 AC: 716 AN: 152138 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00805

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.000755

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00686

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00445 AC: 1120 AN: 251468 AF XY: 0.00465

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00344

Gnomad ASJ exome AF: 0.0134

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00660

Gnomad OTH exome AF: 0.00407

GnomAD4 exome AF: 0.00628 AC: 9185 AN: 1461882 Hom.: 30 Cov.: 31 AF XY: 0.00615 AC XY: 4473 AN XY: 727248

African (AFR) AF: 0.00128 AC: 43 AN: 33480

American (AMR) AF: 0.00380 AC: 170 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0134 AC: 349 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00275 AC: 237 AN: 86258

European-Finnish (FIN) AF: 0.000711 AC: 38 AN: 53420

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.00721 AC: 8020 AN: 1112002

Other (OTH) AF: 0.00502 AC: 303 AN: 60394

GnomAD4 genome AF: 0.00470 AC: 716 AN: 152256 Hom.: 7 Cov.: 32 AF XY: 0.00407 AC XY: 303 AN XY: 74448

African (AFR) AF: 0.00149 AC: 62 AN: 41552

American (AMR) AF: 0.00804 AC: 123 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0110 AC: 38 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.000755 AC: 8 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00687 AC: 467 AN: 68022

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00641 Hom.: 7

Bravo AF: 0.00539

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00802 AC: 69

ExAC AF: 0.00412 AC: 500

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00611

EpiControl AF: 0.00705

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 2 (3)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	NCF2-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	5.7
DANN	Benign	0.39
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.031
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.062
Sift	Benign	0.074	T
Sift4G	Benign	0.086	T
Polyphen		0.0	B
Vest4		0.071
MVP		0.58
MPC		0.31
ClinPred		0.0049	T
GERP RS		1.2
Varity_R		0.044
gMVP		0.30
Mutation Taster		=89/11	polymorphism

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: rs55761650; hg19: chr1-183529339; COSMIC: COSV99055724; COSMIC: COSV99055724;