rs796065031

chr1-183563436-CAGCTT-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000433.4(NCF2):c.1171_1175del(p.Lys391GlufsTer9) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★). 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 1-183563436-CAGCTT-C is Pathogenic according to our data. Variant chr1-183563436-CAGCTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 2242.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-183563436-CAGCTT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCF2	NM_000433.4	c.1171_1175del	p.Lys391GlufsTer9	frameshift_variant	12/15	ENST00000367535.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCF2	ENST00000367535.8	c.1171_1175del	p.Lys391GlufsTer9	frameshift_variant	12/15	1	NM_000433.4	P1

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

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 1999	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 18, 2023	This sequence change creates a premature translational stop signal (p.Lys391Glufs*9) in the NCF2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NCF2 are known to be pathogenic (PMID: 10498624, 20167518). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with chronic granulomatous disease (PMID: 10498624, 33746979). ClinVar contains an entry for this variant (Variation ID: 2242). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

May 30, 2023

Published functional studies demonstrate significantly reduced RNA expression compared with wild type (Patio et al., 1999); Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10498624, 33746979, 20167518) -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs796065031; hg19: chr1-183532571;