chrX-37782132-CCG-GGT

Variant names:

• chrX-37782132-CCG-GGT
• rs387906486
• NM_000397.4:c.90_92delCCGinsGGT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_000397.4(CYBB):​c.90_92delCCGinsGGT​(p.TyrArg30*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CYBB NM_000397.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.49
• Publications: 3 publications found

Genes affected

CYBB (HGNC:2578): (cytochrome b-245 beta chain) Cytochrome b (-245) is composed of cytochrome b alpha (CYBA) and beta (CYBB) chain. It has been proposed as a primary component of the microbicidal oxidase system of phagocytes. CYBB deficiency is one of five described biochemical defects associated with chronic granulomatous disease (CGD). In this disorder, there is decreased activity of phagocyte NADPH oxidase; neutrophils are able to phagocytize bacteria but cannot kill them in the phagocytic vacuoles. The cause of the killing defect is an inability to increase the cell's respiration and consequent failure to deliver activated oxygen into the phagocytic vacuole. [provided by RefSeq, Jul 2008]

CYBB Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, X-linked

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• chronic granulomatous disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency

  Inheritance: XL, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 144 pathogenic variants in the truncated region.
• PP5: Variant X-37782132-CCG-GGT is Pathogenic according to our data. Variant chrX-37782132-CCG-GGT is described in CliVar as Pathogenic. Clinvar id is 10940.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-37782132-CCG-GGT is described in CliVar as Pathogenic. Clinvar id is 10940.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-37782132-CCG-GGT is described in CliVar as Pathogenic. Clinvar id is 10940.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-37782132-CCG-GGT is described in CliVar as Pathogenic. Clinvar id is 10940.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-37782132-CCG-GGT is described in CliVar as Pathogenic. Clinvar id is 10940.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-37782132-CCG-GGT is described in CliVar as Pathogenic. Clinvar id is 10940.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYBB	NM_000397.4	c.90_92delCCGinsGGT	p.TyrArg30*	stop_gained		ENST00000378588.5	NP_000388.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYBB	ENST00000378588.5	c.90_92delCCGinsGGT	p.TyrArg30*	stop_gained		1	NM_000397.4	ENSP00000367851.4
ENSG00000250349	ENST00000465127.1	c.171+356132_171+356134delCCGinsGGT		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

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

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Granulomatous disease, chronic, X-linked Pathogenic:1

Jan 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs387906486; hg19: chrX-37641385;