rs35080474

Variant names:

• chrX-37796121-C-A
• rs35080474
• NM_000397.4:c.654C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000397.4(CYBB):​c.654C>A​(p.Gly218Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,206,526 control chromosomes in the GnomAD database, including 1 homozygotes. There are 156 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., 71 hem., cov: 22)
  • Exomes 𝑓: 0.00032 (0 hom. 85 hem.)
• Consequence: CYBB NM_000397.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.99
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-37796121-C-A is Benign according to our data. Variant chrX-37796121-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35975.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 = 0.00282 (315/111813) while in subpopulation AFR AF = 0.00964 (297/30818). AF 95% confidence interval is 0.00874. There are 1 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 71 XL,AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000397.4. 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
	CYBB	NM_000397.4	MANE Select	c.654C>A	p.Gly218Gly	synonymous	Exon 6 of 13	NP_000388.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBB	ENST00000378588.5	TSL:1 MANE Select	c.654C>A	p.Gly218Gly	synonymous	Exon 6 of 13	ENSP00000367851.4	P04839
	ENSG00000250349	ENST00000465127.1	TSL:5	c.171+370121C>A		intron	N/A	ENSP00000417050.1	B4E171
	CYBB	ENST00000968558.1		c.654C>A	p.Gly218Gly	synonymous	Exon 6 of 14	ENSP00000638617.1

Frequencies

GnomAD3 genomes AF: 0.00283 AC: 316 AN: 111757 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00969

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00133

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000368

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00199

GnomAD2 exomes AF: 0.000826 AC: 151 AN: 182763 AF XY: 0.000533

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000315 AC: 345 AN: 1094713 Hom.: 0 Cov.: 31 AF XY: 0.000236 AC XY: 85 AN XY: 360521

African (AFR) AF: 0.0116 AC: 304 AN: 26291

American (AMR) AF: 0.000513 AC: 18 AN: 35117

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19345

East Asian (EAS) AF: 0.00 AC: 0 AN: 30189

South Asian (SAS) AF: 0.00 AC: 0 AN: 54073

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40503

Middle Eastern (MID) AF: 0.000243 AC: 1 AN: 4122

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 839122

Other (OTH) AF: 0.000457 AC: 21 AN: 45951

GnomAD4 genome AF: 0.00282 AC: 315 AN: 111813 Hom.: 1 Cov.: 22 AF XY: 0.00208 AC XY: 71 AN XY: 34063

African (AFR) AF: 0.00964 AC: 297 AN: 30818

American (AMR) AF: 0.00133 AC: 14 AN: 10547

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2643

East Asian (EAS) AF: 0.00 AC: 0 AN: 3525

South Asian (SAS) AF: 0.000369 AC: 1 AN: 2710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6052

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53090

Other (OTH) AF: 0.00197 AC: 3 AN: 1525

Alfa AF: 0.00145 Hom.: 14

Bravo AF: 0.00348

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Granulomatous disease, chronic, X-linked (2)
-	-	1	CYBB-related disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	3.6
DANN	Benign	0.70
PhyloP100		-2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs35080474; hg19: chrX-37655374;