X-37804069-G-C

Variant names:

• chrX-37804069-G-C
• rs141756032
• NM_000397.4:c.1090G>C

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.1090G>C​(p.Gly364Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00497 in 1,208,693 control chromosomes in the GnomAD database, including 16 homozygotes. There are 1,993 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G364V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., 102 hem., cov: 22)
  • Exomes 𝑓: 0.0051 (14 hom. 1891 hem.)
• Consequence: CYBB NM_000397.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 3.80
• Publications: 17 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 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000397.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.014557958).
• BP6: Variant X-37804069-G-C is Benign according to our data. Variant chrX-37804069-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 68372.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 = 0.0036 (401/111277) while in subpopulation NFE AF = 0.00589 (312/52969). AF 95% confidence interval is 0.00535. There are 2 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1090G>C	p.Gly364Arg	missense	Exon 9 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.1090G>C	p.Gly364Arg	missense	Exon 9 of 13	ENSP00000367851.4	P04839
	ENSG00000250349	ENST00000465127.1	TSL:5	c.171+378069G>C		intron	N/A	ENSP00000417050.1	B4E171
	CYBB	ENST00000968558.1		c.1090G>C	p.Gly364Arg	missense	Exon 9 of 14	ENSP00000638617.1

Frequencies

GnomAD3 genomes AF: 0.00361 AC: 401 AN: 111226 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.000589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00200

Gnomad ASJ AF: 0.00152

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00114

Gnomad FIN AF: 0.00583

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00589

Gnomad OTH AF: 0.00537

GnomAD2 exomes AF: 0.00394 AC: 721 AN: 182856 AF XY: 0.00437

Gnomad AFR exome AF: 0.000532

Gnomad AMR exome AF: 0.000988

Gnomad ASJ exome AF: 0.00294

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00544

Gnomad NFE exome AF: 0.00637

Gnomad OTH exome AF: 0.00422

GnomAD4 exome AF: 0.00510 AC: 5601 AN: 1097416 Hom.: 14 Cov.: 31 AF XY: 0.00521 AC XY: 1891 AN XY: 362990

African (AFR) AF: 0.000417 AC: 11 AN: 26372

American (AMR) AF: 0.00102 AC: 36 AN: 35130

Ashkenazi Jewish (ASJ) AF: 0.00351 AC: 68 AN: 19367

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30196

South Asian (SAS) AF: 0.00238 AC: 129 AN: 54140

European-Finnish (FIN) AF: 0.00587 AC: 238 AN: 40526

Middle Eastern (MID) AF: 0.00145 AC: 6 AN: 4127

European-Non Finnish (NFE) AF: 0.00588 AC: 4949 AN: 841503

Other (OTH) AF: 0.00352 AC: 162 AN: 46055

GnomAD4 genome AF: 0.00360 AC: 401 AN: 111277 Hom.: 2 Cov.: 22 AF XY: 0.00304 AC XY: 102 AN XY: 33531

African (AFR) AF: 0.000588 AC: 18 AN: 30618

American (AMR) AF: 0.00200 AC: 21 AN: 10497

Ashkenazi Jewish (ASJ) AF: 0.00152 AC: 4 AN: 2640

East Asian (EAS) AF: 0.00 AC: 0 AN: 3509

South Asian (SAS) AF: 0.00114 AC: 3 AN: 2631

European-Finnish (FIN) AF: 0.00583 AC: 35 AN: 5999

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

European-Non Finnish (NFE) AF: 0.00589 AC: 312 AN: 52969

Other (OTH) AF: 0.00530 AC: 8 AN: 1509

Alfa AF: 0.00543 Hom.: 114

Bravo AF: 0.00301

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00312 AC: 9

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00505 AC: 34

ExAC AF: 0.00430 AC: 522

EpiCase AF: 0.00480

EpiControl AF: 0.00706

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)
-	-	2	not provided (3)
-	-	1	Granulomatous disease, chronic, X-linked;C1970859:X-linked Mendelian susceptibility to mycobacterial diseases due to CYBB deficiency (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.015	T
MetaSVM	Uncertain	0.088	D
MutationAssessor	Benign	-0.29	N
PhyloP100		3.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.49
Sift	Benign	0.37	T
Sift4G	Benign	0.55	T
Polyphen		0.98	D
Vest4		0.19
MutPred		0.18		Gain of solvent accessibility (P = 0.0674)
MVP		0.94
MPC		1.3
ClinPred		0.013	T
GERP RS		5.8
Varity_R		0.62
gMVP		0.91
Mutation Taster		=95/5	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs141756032; hg19: chrX-37663322; COSMIC: COSV66085331;