rs760275837

chr16-88643411-C-CCCG

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PM4_Supporting BP6 BS1

The NM_000101.4(CYBA):c.529_530insCGG(p.Ala176dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00067 in 1,534,392 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G177G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00070 (0 hom.)
• Consequence: CYBA NM_000101.4 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.94

Genes affected

CYBA (HGNC:2577): (cytochrome b-245 alpha chain) Cytochrome b is comprised of a light chain (alpha) and a heavy chain (beta). This gene encodes the light, alpha subunit which has been proposed as a primary component of the microbicidal oxidase system of phagocytes. Mutations in this gene are associated with autosomal recessive chronic granulomatous disease (CGD), that is characterized by the failure of activated phagocytes to generate superoxide, which is important for the microbicidal activity of these cells. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000101.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 16-88643411-C-CCCG is Benign according to our data. Variant chr16-88643411-C-CCCG is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 418151.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=4, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000427 (65/152070) while in subpopulation NFE AF= 0.000574 (39/67970). AF 95% confidence interval is 0.000431. There are 0 homozygotes in gnomad4. There are 33 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYBA	NM_000101.4	c.529_530insCGG	p.Ala176dup	inframe_insertion	6/6	ENST00000261623.8
CYBA	XM_011522905.4	c.*1754_*1755insCGG		3_prime_UTR_variant	6/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYBA	ENST00000261623.8	c.529_530insCGG	p.Ala176dup	inframe_insertion	6/6	1	NM_000101.4	P1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152070 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000566

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000284 AC: 36 AN: 126554 Hom.: 0 AF XY: 0.000259 AC XY: 18 AN XY: 69630

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000838

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.000613

Gnomad OTH exome AF: 0.000261

GnomAD4 exome AF: 0.000697 AC: 963 AN: 1382322 Hom.: 0 Cov.: 32 AF XY: 0.000666 AC XY: 454 AN XY: 681880

Gnomad4 AFR exome AF: 0.0000993

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000921

Gnomad4 NFE exome AF: 0.000809

Gnomad4 OTH exome AF: 0.000819

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152070 Hom.: 0 Cov.: 33 AF XY: 0.000444 AC XY: 33 AN XY: 74290

Gnomad4 AFR AF: 0.000314

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000566

Gnomad4 NFE AF: 0.000574

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000633 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 17, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 09, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2021	- -

Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	CYBA NM_000101.3 exon 6 p.Ala176dup (c.527_529dup): This variant has not been reported in the literature but is present in 33/51894 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs760275837). This variant is present in ClinVar (Variation ID:418151). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant represents a duplication of 1 amino acid at position 176 and is not predicted to alter the reading frame. However, the effect of this variant on the protein is unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This variant, c.527_529dup, results in the insertion of 1 amino acid(s) of the CYBA protein (p.Ala176dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760275837, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with CYBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 418151). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Chronic granulomatous disease Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 17, 2020

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 23, 2024

Variant summary: CYBA c.527_529dupCGG (p.Ala176dup) results in an in-frame duplication that is predicted to duplicate one amino acids into the encoded protein. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.29 fold of the estimated maximal expected allele frequency for a pathogenic variant in CYBA causing Chronic Granulomatous Disease phenotype (0.00061), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.527_529dupCGG in individuals affected with Chronic Granulomatous Disease and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 418151). Based on the evidence outlined above, the variant was classified as likely benign. -

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: rs760275837; hg19: chr16-88709819;