17-4156963-C-A

Variant names:

• chr17-4156963-C-A
• rs750306451
• NM_144611.4:c.676C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_144611.4(CYB5D2):​c.676C>A​(p.Pro226Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,460,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: CYB5D2 NM_144611.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03
• Publications: 0 publications found

Genes affected

CYB5D2 (HGNC:28471): (cytochrome b5 domain containing 2) Predicted to enable heme binding activity. Predicted to be involved in nervous system development. Predicted to act upstream of or within positive regulation of neuron differentiation. Predicted to be located in extracellular region. Predicted to be active in endomembrane system and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000308322 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3492336).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144611.4. 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
	CYB5D2	NM_144611.4	MANE Select	c.676C>A	p.Pro226Thr	missense	Exon 4 of 4	NP_653212.1	Q8WUJ1-1
	CYB5D2	NM_001254755.2		c.340C>A	p.Pro114Thr	missense	Exon 4 of 4	NP_001241684.1	Q8WUJ1-3
	CYB5D2	NM_001254756.1		c.340C>A	p.Pro114Thr	missense	Exon 4 of 4	NP_001241685.1	Q8WUJ1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5D2	ENST00000301391.8	TSL:1 MANE Select	c.676C>A	p.Pro226Thr	missense	Exon 4 of 4	ENSP00000301391.4	Q8WUJ1-1
	CYB5D2	ENST00000575251.5	TSL:2	c.340C>A	p.Pro114Thr	missense	Exon 4 of 4	ENSP00000458903.1	Q8WUJ1-3
	CYB5D2	ENST00000577075.6	TSL:2	c.340C>A	p.Pro114Thr	missense	Exon 4 of 4	ENSP00000458352.2	Q8WUJ1-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251328 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460532 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 726568

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86182

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4650

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112004

Other (OTH) AF: 0.0000166 AC: 1 AN: 60282

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions as Germline

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	Benign	0.15
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.0
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.40
Sift	Benign	0.097	T
Sift4G	Benign	0.064	T
Polyphen		0.92	P
Vest4		0.63
MutPred		0.18		Loss of catalytic residue at P225 (P = 0.0318)
MVP		0.41
MPC		0.53
ClinPred		0.93	D
GERP RS		5.1
Varity_R		0.16
gMVP		0.52
Mutation Taster		=63/37	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

dbSNP: rs750306451; hg19: chr17-4060257;