NM_016229.5:c.452G>A

Variant names:

• chr11-7668498-C-T
• NM_016229.5:c.452G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_016229.5(CYB5R2):​c.452G>A​(p.Gly151Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,804 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CYB5R2 NM_016229.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.60
• Publications: 0 publications found

Genes affected

CYB5R2 (HGNC:24376): (cytochrome b5 reductase 2) The protein encoded by this gene belongs to the flavoprotein pyridine nucleotide cytochrome reductase family of proteins. Cytochrome b-type NAD(P)H oxidoreductases are implicated in many processes including cholesterol biosynthesis, fatty acid desaturation and elongation, and respiratory burst in neutrophils and macrophages. Cytochrome b5 reductases have soluble and membrane-bound forms that are the product of alternative splicing. In animal cells, the membrane-bound form binds to the endoplasmic reticulum, where it is a member of a fatty acid desaturation complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016229.5. 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
	CYB5R2	NM_016229.5	MANE Select	c.452G>A	p.Gly151Glu	missense	Exon 6 of 9	NP_057313.2
	CYB5R2	NM_001302826.2		c.452G>A	p.Gly151Glu	missense	Exon 6 of 9	NP_001289755.1	Q6BCY4-1
	CYB5R2	NM_001302827.1		c.452G>A	p.Gly151Glu	missense	Exon 5 of 8	NP_001289756.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5R2	ENST00000299498.11	TSL:1 MANE Select	c.452G>A	p.Gly151Glu	missense	Exon 6 of 9	ENSP00000299498.6	Q6BCY4-1
	CYB5R2	ENST00000524790.5	TSL:1	c.452G>A	p.Gly151Glu	missense	Exon 6 of 10	ENSP00000435916.1	Q6BCY4-2
	CYB5R2	ENST00000917897.1		c.518G>A	p.Gly173Glu	missense	Exon 6 of 9	ENSP00000587956.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461804 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.6
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.54		Gain of catalytic residue at G151 (P = 0.0472)
MVP		0.94
MPC		0.032
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.97
gMVP		0.95
Mutation Taster		=53/47	polymorphism

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

hg19: chr11-7689729;