Genetic Variant CYB5D2:p.Ala19Val (chr17-4143811-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_144611.4(CYB5D2):c.56C>T(p.Ala19Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

CYB5D2
NM_144611.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.14

Variant links:

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]

CYB5D2 links:

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ACMG classification

Classification made for transcript

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=0.09246531).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYB5D2	NM_144611.4 link	c.56C>T	p.Ala19Val	missense_variant	Exon 1 of 4	ENST00000301391.8	NP_653212.1	Q8WUJ1-1
CYB5D2	NM_001254755.2 link	c.-87+48C>T		intron_variant	Intron 1 of 3		NP_001241684.1	Q8WUJ1-3
CYB5D2	NM_001254756.1 link	c.-87+498C>T		intron_variant	Intron 1 of 3		NP_001241685.1	Q8WUJ1-3
CYB5D2	XM_047435333.1 link	c.-87+577C>T		intron_variant	Intron 1 of 3		XP_047291289.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CYB5D2	ENST00000301391.8 link	c.56C>T	p.Ala19Val	missense_variant	Exon 1 of 4	1	NM_144611.4	ENSP00000301391.4	Q8WUJ1-1
CYB5D2	ENST00000575251.5 link	c.-87+48C>T		intron_variant	Intron 1 of 3	2		ENSP00000458903.1	Q8WUJ1-3
CYB5D2	ENST00000577075.6 link	c.-87+498C>T		intron_variant	Intron 1 of 3	2		ENSP00000458352.2	Q8WUJ1-3
CYB5D2	ENST00000573984.1 link	c.-87+48C>T		intron_variant	Intron 1 of 3	4		ENSP00000461090.1	I3L497

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000438

AC:

AN:

251324

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135844

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000544

Gnomad SAS 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:

0.00000889

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152340

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ExAC

AF:

0.0000576

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 31, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.56C>T (p.A19V) alteration is located in exon 1 (coding exon 1) of the CYB5D2 gene. This alteration results from a C to T substitution at nucleotide position 56, causing the alanine (A) at amino acid position 19 to be replaced by a valine (V). 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

0.11

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.50

M_CAP

Uncertain

0.087

MetaRNN

Benign

0.092

MetaSVM

Benign

-0.79

MutationAssessor

Uncertain

2.0

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.15

REVEL

Benign

0.20

Sift

Benign

0.033

Sift4G

Benign

0.63

Polyphen

0.79

Vest4

0.24

MutPred

0.35

Gain of catalytic residue at A19 (P = 0.071);

MVP

0.62

MPC

0.14

ClinPred

0.11

GERP RS

3.7

Varity_R

0.084

gMVP

0.78

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over