rs796065031

Variant names:

• chr1-183563436-CAGCTT-C
• rs796065031
• NM_000433.4:c.1171_1175delAAGCT

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000433.4(NCF2):​c.1171_1175delAAGCT​(p.Lys391GlufsTer9) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001820392: Published functional studies demonstrate significantly reduced RNA expression compared with wild type (Patio et al., 1999)" and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. K391K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCF2 NM_000433.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.90
• Publications: 2 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV001820392: Published functional studies demonstrate significantly reduced RNA expression compared with wild type (Patio et al., 1999); PMID: 10498624
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-183563436-CAGCTT-C is Pathogenic according to our data. Variant chr1-183563436-CAGCTT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1171_1175delAAGCT	p.Lys391GlufsTer9	frameshift	Exon 12 of 15	NP_000424.2	P19878-1
	NCF2	NM_001127651.3		c.1171_1175delAAGCT	p.Lys391GlufsTer9	frameshift	Exon 13 of 16	NP_001121123.1	P19878-1
	NCF2	NM_001410895.1		c.1063_1067delAAGCT	p.Lys355GlufsTer9	frameshift	Exon 12 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.1171_1175delAAGCT	p.Lys391GlufsTer9	frameshift	Exon 12 of 15	ENSP00000356505.4	P19878-1
	NCF2	ENST00000367536.5	TSL:1	c.1171_1175delAAGCT	p.Lys391GlufsTer9	frameshift	Exon 13 of 16	ENSP00000356506.1	P19878-1
	NCF2	ENST00000946295.1		c.1171_1175delAAGCT	p.Lys391GlufsTer9	frameshift	Exon 12 of 16	ENSP00000616354.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

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
PhyloP100		6.9
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs796065031; hg19: chr1-183532571;