chr16-69448115-A-G

Position:

• chr16-69448115-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_030579.3(CYB5B):​c.304A>G​(p.Ser102Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYB5B NM_030579.3 missense, splice_region
• Scores: Splicing: ADA: 0.00006281
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.782

Genes affected

CYB5B (HGNC:24374): (cytochrome b5 type B) Enables heme binding activity. Contributes to nitrite reductase (NO-forming) activity. Involved in nitric oxide biosynthetic process. Located in membrane. Part of nitric-oxide synthase complex. [provided by Alliance of Genome Resources, Apr 2022]

CYB5B (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1282618).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYB5B	NM_030579.3	c.304A>G	p.Ser102Gly	missense_variant, splice_region_variant	3/5	ENST00000307892.13	NP_085056.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYB5B	ENST00000307892.13	c.304A>G	p.Ser102Gly	missense_variant, splice_region_variant	3/5	1	NM_030579.3	ENSP00000308430.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2023

The c.304A>G (p.S102G) alteration is located in exon 3 (coding exon 3) of the CYB5B gene. This alteration results from a A to G substitution at nucleotide position 304, causing the serine (S) at amino acid position 102 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.057	T;.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.72	T;T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.010	D;D;D
Sift4G	Uncertain	0.037	D;D;T
Polyphen		0.018	B;.;.
Vest4		0.18
MutPred		0.21		Loss of phosphorylation at S98 (P = 0.0467);.;Loss of phosphorylation at S98 (P = 0.0467);
MVP		0.79
MPC		0.14
ClinPred		0.50	D
GERP RS		3.0
Varity_R		0.23
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000063
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs868215802; hg19: chr16-69482018;