11-7666528-C-T

Variant summary

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

The NM_016229.5(CYB5R2):​c.581G>A​(p.Arg194Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,274 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CYB5R2
NM_016229.5 missense

Scores

11
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.98
Variant links:
Genes affected
CYB5R2 (HGNC:24376): (cytochrome b5 reductase 2) The protein encoded by this gene belongs to the flavoprotein pyridine nucleotide cytochrome reductase family of proteins. Cytochrome b-type NAD(P)H oxidoreductases are implicated in many processes including cholesterol biosynthesis, fatty acid desaturation and elongation, and respiratory burst in neutrophils and macrophages. Cytochrome b5 reductases have soluble and membrane-bound forms that are the product of alternative splicing. In animal cells, the membrane-bound form binds to the endoplasmic reticulum, where it is a member of a fatty acid desaturation complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]
PPFIBP2 (HGNC:9250): (PPFIA binding protein 2) This gene encodes a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. The encoded protein is a beta liprin and plays a role in axon guidance and neuronal synapse development by recruiting LAR protein-tyrosine phosphatases to the plasma membrane. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
CYB5R2NM_016229.5 linkc.581G>A p.Arg194Lys missense_variant Exon 8 of 9 ENST00000299498.11 NP_057313.2 Q6BCY4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYB5R2ENST00000299498.11 linkc.581G>A p.Arg194Lys missense_variant Exon 8 of 9 1 NM_016229.5 ENSP00000299498.6 Q6BCY4-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251426
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.00000137
AC:
2
AN:
1461274
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726962
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 07, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.581G>A (p.R194K) alteration is located in exon 8 (coding exon 7) of the CYB5R2 gene. This alteration results from a G to A substitution at nucleotide position 581, causing the arginine (R) at amino acid position 194 to be replaced by a lysine (K). 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
0.16
BayesDel_addAF
Uncertain
0.050
T
BayesDel_noAF
Uncertain
-0.080
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.28
.;T;T
Eigen
Uncertain
0.40
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.92
D;.;D
M_CAP
Benign
0.043
D
MetaRNN
Uncertain
0.62
D;D;D
MetaSVM
Uncertain
0.12
D
MutationAssessor
Benign
1.6
L;L;L
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-2.8
D;D;D
REVEL
Uncertain
0.57
Sift
Benign
0.10
T;T;T
Sift4G
Benign
0.28
T;T;T
Polyphen
0.69
.;P;P
Vest4
0.35
MutPred
0.76
Gain of methylation at R194 (P = 0.0089);Gain of methylation at R194 (P = 0.0089);Gain of methylation at R194 (P = 0.0089);
MVP
0.91
MPC
0.013
ClinPred
0.93
D
GERP RS
4.7
Varity_R
0.64
gMVP
0.79

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs1290002446; hg19: chr11-7687759; API