16-88646805-C-G

Variant names:

• chr16-88646805-C-G
• rs2228472
• NM_000101.4:c.237G>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000101.4(CYBA):​c.237G>C​(p.Leu79Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00747 in 1,613,928 control chromosomes in the GnomAD database, including 795 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L79L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (409 hom., cov: 33)
  • Exomes 𝑓: 0.0040 (386 hom.)
• Consequence: CYBA NM_000101.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00300
• Publications: 3 publications found

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]

CYBA Gene-Disease associations (from GenCC):

• granulomatous disease, chronic, autosomal recessive, cytochrome b-negative

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016738176).
• BP6: Variant 16-88646805-C-G is Benign according to our data. Variant chr16-88646805-C-G is described in ClinVar as Benign. ClinVar VariationId is 255126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.003 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000101.4. 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
	CYBA	NM_000101.4	MANE Select	c.237G>C	p.Leu79Leu	synonymous	Exon 4 of 6	NP_000092.2	P13498

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYBA	ENST00000261623.8	TSL:1 MANE Select	c.237G>C	p.Leu79Leu	synonymous	Exon 4 of 6	ENSP00000261623.3	P13498
	CYBA	ENST00000569359.5	TSL:1	c.237G>C	p.Leu79Leu	synonymous	Exon 4 of 5	ENSP00000456079.1	H3BR52
	CYBA	ENST00000696161.1		c.367G>C	p.Val123Leu	missense	Exon 4 of 6	ENSP00000512451.1	A0A8Q3WL26

Frequencies

GnomAD3 genomes AF: 0.0406 AC: 6174 AN: 152078 Hom.: 407 Cov.: 33

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.0102 AC: 2562 AN: 251036 AF XY: 0.00763

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.00654

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00402 AC: 5874 AN: 1461732 Hom.: 386 Cov.: 31 AF XY: 0.00339 AC XY: 2463 AN XY: 727192

African (AFR) AF: 0.146 AC: 4890 AN: 33472

American (AMR) AF: 0.00693 AC: 310 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000336 AC: 29 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0000710 AC: 79 AN: 1111974

Other (OTH) AF: 0.00911 AC: 550 AN: 60392

GnomAD4 genome AF: 0.0406 AC: 6182 AN: 152196 Hom.: 409 Cov.: 33 AF XY: 0.0392 AC XY: 2915 AN XY: 74408

African (AFR) AF: 0.142 AC: 5876 AN: 41490

American (AMR) AF: 0.0144 AC: 220 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00145 AC: 7 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68012

Other (OTH) AF: 0.0265 AC: 56 AN: 2114

Alfa AF: 0.00444 Hom.: 19

Bravo AF: 0.0460

ESP6500AA AF: 0.143 AC: 627

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0126 AC: 1536

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Chronic granulomatous disease (1)
-	-	1	Granulomatous disease, chronic, autosomal recessive, cytochrome b-negative (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.8
DANN	Benign	0.87
FATHMM_MKL	Benign	0.54	D
MetaRNN	Benign	0.0017	T
PhyloP100		0.0030
PROVEAN	Benign	-1.7	N
GERP RS		0.68
PromoterAI		-0.038	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	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: rs2228472; hg19: chr16-88713213;