NM_000397.4:c.1551T>A

Variant names:

• chrX-37809656-T-A
• rs151344452
• NM_000397.4:c.1551T>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000397.4(CYBB):​c.1551T>A​(p.Asp517Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00208 in 1,207,338 control chromosomes in the GnomAD database, including 4 homozygotes. There are 776 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D517Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., 42 hem., cov: 23)
  • Exomes 𝑓: 0.0022 (3 hom. 734 hem.)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 1.26
• Publications: 7 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 8 uncertain in NM_000397.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.018161982).
• BP6: Variant X-37809656-T-A is Benign according to our data. Variant chrX-37809656-T-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 68385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00139 (156/111849) while in subpopulation NFE AF = 0.00252 (134/53122). AF 95% confidence interval is 0.00217. There are 1 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 42 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.1551T>A	p.Asp517Glu	missense	Exon 12 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.1551T>A	p.Asp517Glu	missense	Exon 12 of 13	ENSP00000367851.4	P04839
	ENSG00000250349	ENST00000465127.1	TSL:5	c.171+383656T>A		intron	N/A	ENSP00000417050.1	B4E171
	CYBB	ENST00000968558.1		c.1551T>A	p.Asp517Glu	missense	Exon 12 of 14	ENSP00000638617.1

Frequencies

GnomAD3 genomes AF: 0.00139 AC: 155 AN: 111796 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.000228

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000762

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00149

Gnomad FIN AF: 0.000164

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00252

Gnomad OTH AF: 0.000666

GnomAD2 exomes AF: 0.00118 AC: 209 AN: 176958 AF XY: 0.00108

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.000446

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000193

Gnomad NFE exome AF: 0.00219

Gnomad OTH exome AF: 0.000227

GnomAD4 exome AF: 0.00215 AC: 2360 AN: 1095489 Hom.: 3 Cov.: 30 AF XY: 0.00203 AC XY: 734 AN XY: 361337

African (AFR) AF: 0.000228 AC: 6 AN: 26354

American (AMR) AF: 0.000400 AC: 14 AN: 34998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19316

East Asian (EAS) AF: 0.00 AC: 0 AN: 30167

South Asian (SAS) AF: 0.00105 AC: 56 AN: 53512

European-Finnish (FIN) AF: 0.000272 AC: 11 AN: 40378

Middle Eastern (MID) AF: 0.000484 AC: 2 AN: 4133

European-Non Finnish (NFE) AF: 0.00263 AC: 2208 AN: 840637

Other (OTH) AF: 0.00137 AC: 63 AN: 45994

GnomAD4 genome AF: 0.00139 AC: 156 AN: 111849 Hom.: 1 Cov.: 23 AF XY: 0.00123 AC XY: 42 AN XY: 34051

African (AFR) AF: 0.000227 AC: 7 AN: 30818

American (AMR) AF: 0.000761 AC: 8 AN: 10507

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.000281 AC: 1 AN: 3558

South Asian (SAS) AF: 0.00150 AC: 4 AN: 2672

European-Finnish (FIN) AF: 0.000164 AC: 1 AN: 6094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.00252 AC: 134 AN: 53122

Other (OTH) AF: 0.000658 AC: 1 AN: 1520

Alfa AF: 0.00120 Hom.: 9

Bravo AF: 0.00113

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00242 AC: 7

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.00223 AC: 15

ExAC AF: 0.00134 AC: 162

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (4)
-	-	2	not specified (2)
-	-	1	CYBB-related disorder (1)
-	-	1	Granulomatous disease, chronic, X-linked (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.76	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.72	N
PhyloP100		1.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.31
Sift	Benign	0.23	T
Sift4G	Benign	0.21	T
Polyphen		0.0040	B
Vest4		0.048
MutPred		0.17		Loss of loop (P = 0.0804)
MVP		0.92
MPC		0.57
ClinPred		0.016	T
GERP RS		3.3
Varity_R		0.35
gMVP		0.74
Mutation Taster		=78/21	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs151344452; hg19: chrX-37668909;