1-183590148-C-G

Variant names:

• chr1-183590148-C-G
• rs34009795
• NM_000433.4:c.174+8G>C

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.174+8G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,614,160 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0052 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (8 hom.)
• Consequence: NCF2 NM_000433.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001977
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.67
• Publications: 0 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 (BayesDel_noAF=-0.71).
• BP6: Variant 1-183590148-C-G is Benign according to our data. Variant chr1-183590148-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 294086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00517 (787/152282) while in subpopulation AFR AF = 0.0175 (726/41546). AF 95% confidence interval is 0.0164. There are 4 homozygotes in GnomAd4. There are 358 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.174+8G>C		splice_region intron	N/A	NP_000424.2
	NCF2	NM_001127651.3		c.174+8G>C		splice_region intron	N/A	NP_001121123.1
	NCF2	NM_001410895.1		c.174+8G>C		splice_region intron	N/A	NP_001397824.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCF2	ENST00000367535.8	TSL:1 MANE Select	c.174+8G>C		splice_region intron	N/A	ENSP00000356505.4
	NCF2	ENST00000367536.5	TSL:1	c.174+8G>C		splice_region intron	N/A	ENSP00000356506.1
	NCF2	ENST00000946295.1		c.174+8G>C		splice_region intron	N/A	ENSP00000616354.1

Frequencies

GnomAD3 genomes AF: 0.00519 AC: 790 AN: 152164 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00152 AC: 382 AN: 251090 AF XY: 0.00114

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000720 AC: 1053 AN: 1461878 Hom.: 8 Cov.: 31 AF XY: 0.000638 AC XY: 464 AN XY: 727242

African (AFR) AF: 0.0189 AC: 633 AN: 33476

American (AMR) AF: 0.00103 AC: 46 AN: 44724

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

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53416

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.000238 AC: 265 AN: 1112008

Other (OTH) AF: 0.00152 AC: 92 AN: 60396

GnomAD4 genome AF: 0.00517 AC: 787 AN: 152282 Hom.: 4 Cov.: 32 AF XY: 0.00481 AC XY: 358 AN XY: 74462

African (AFR) AF: 0.0175 AC: 726 AN: 41546

American (AMR) AF: 0.00157 AC: 24 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68030

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00152 Hom.: 0

Bravo AF: 0.00559

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000771

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	0.49
DANN	Benign	0.77
PhyloP100		-1.7
PromoterAI		-0.17	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00020
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs34009795; hg19: chr1-183559283;