17-4143808-C-G

Variant names:

• chr17-4143808-C-G
• rs1224650528
• NM_144611.4:c.53C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144611.4(CYB5D2):​c.53C>G​(p.Ala18Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. A18V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYB5D2 NM_144611.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.163
• 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]

ZZEF1 (HGNC:29027): (zinc finger ZZ-type and EF-hand domain containing 1) Predicted to enable ubiquitin-like protein ligase activity. Predicted to act upstream of or within several processes, including glutamatergic synaptic transmission; regulation of peptidyl-tyrosine phosphorylation; and visual learning. Predicted to be located in cell surface; postsynapse; and presynaptic active zone. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21651533).

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.53C>G	p.Ala18Gly	missense	Exon 1 of 4	NP_653212.1	Q8WUJ1-1
	CYB5D2	NM_001254755.2		c.-87+45C>G		intron	N/A	NP_001241684.1	Q8WUJ1-3
	CYB5D2	NM_001254756.1		c.-87+495C>G		intron	N/A	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.53C>G	p.Ala18Gly	missense	Exon 1 of 4	ENSP00000301391.4	Q8WUJ1-1
	CYB5D2	ENST00000575251.5	TSL:2	c.-87+45C>G		intron	N/A	ENSP00000458903.1	Q8WUJ1-3
	CYB5D2	ENST00000577075.6	TSL:2	c.-87+495C>G		intron	N/A	ENSP00000458352.2	Q8WUJ1-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461762 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727168

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5736

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111974

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.028	N
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.16
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.25
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.013	D
Polyphen		0.82	P
Vest4		0.24
MutPred		0.39		Gain of catalytic residue at A17 (P = 0.0877)
MVP		0.53
MPC		0.14
ClinPred		1.0	D
GERP RS		2.6
PromoterAI		-0.034	Neutral
Varity_R		0.086
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1224650528; hg19: chr17-4047102;