chr17-4143811-C-A

Variant names:

• chr17-4143811-C-A
• rs750462585
• NM_144611.4:c.56C>A

Variant summary

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

The NM_144611.4(CYB5D2):​c.56C>A​(p.Ala19Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A19V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CYB5D2 NM_144611.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5D2	NM_144611.4	c.56C>A	p.Ala19Glu	missense_variant	Exon 1 of 4	ENST00000301391.8	NP_653212.1
CYB5D2	NM_001254755.2	c.-87+48C>A		intron_variant	Intron 1 of 3		NP_001241684.1
CYB5D2	NM_001254756.1	c.-87+498C>A		intron_variant	Intron 1 of 3		NP_001241685.1
CYB5D2	XM_047435333.1	c.-87+577C>A		intron_variant	Intron 1 of 3		XP_047291289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5D2	ENST00000301391.8	c.56C>A	p.Ala19Glu	missense_variant	Exon 1 of 4	1	NM_144611.4	ENSP00000301391.4
CYB5D2	ENST00000575251.5	c.-87+48C>A		intron_variant	Intron 1 of 3	2		ENSP00000458903.1
CYB5D2	ENST00000577075.6	c.-87+498C>A		intron_variant	Intron 1 of 3	2		ENSP00000458352.2
CYB5D2	ENST00000573984.1	c.-87+48C>A		intron_variant	Intron 1 of 3	4		ENSP00000461090.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251324 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135844

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461778 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727184

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.015	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.13
Eigen_PC	Benign	0.049
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.41	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.0	M
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.38	N
REVEL	Uncertain	0.39
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.56		Loss of MoRF binding (P = 0.0393);
MVP		0.67
MPC		0.16
ClinPred		0.67	D
GERP RS		3.7
Varity_R		0.19
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs750462585; hg19: chr17-4047105;