NM_144611.4:c.19C>T

Variant names:

• chr17-4143774-C-T
• rs200936057
• NM_144611.4:c.19C>T

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.19C>T​(p.Arg7Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000124 in 1,613,810 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., 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: 0.461
• 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=0.107248336).

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.19C>T	p.Arg7Cys	missense	Exon 1 of 4	NP_653212.1	Q8WUJ1-1
	CYB5D2	NM_001254755.2		c.-87+11C>T		intron	N/A	NP_001241684.1	Q8WUJ1-3
	CYB5D2	NM_001254756.1		c.-87+461C>T		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.19C>T	p.Arg7Cys	missense	Exon 1 of 4	ENSP00000301391.4	Q8WUJ1-1
	CYB5D2	ENST00000575251.5	TSL:2	c.-87+11C>T		intron	N/A	ENSP00000458903.1	Q8WUJ1-3
	CYB5D2	ENST00000577075.6	TSL:2	c.-87+461C>T		intron	N/A	ENSP00000458352.2	Q8WUJ1-3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251030 AF XY: 0.0000369

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461470 Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11 AN XY: 727028

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.000179 AC: 8 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5656

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111886

Other (OTH) AF: 0.0000497 AC: 3 AN: 60356

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74500

African (AFR) AF: 0.0000240 AC: 1 AN: 41592

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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	Benign	0.30
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	15
DANN	Benign	0.88
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0085	N
LIST_S2	Benign	0.60	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	2.0	M
PhyloP100		0.46
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.19
Sift	Benign	0.041	D
Sift4G	Uncertain	0.026	D
Polyphen		0.016	B
Vest4		0.29
MVP		0.095
MPC		0.19
ClinPred		0.095	T
GERP RS		-1.2
PromoterAI		-0.059	Neutral
Varity_R		0.062
gMVP		0.76
Mutation Taster		=93/7	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs200936057; hg19: chr17-4047068;