chr18-74263351-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_148923.4(CYB5A):c.256C>T(p.Pro86Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000031 in 1,613,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
CYB5A
NM_148923.4 missense, splice_region
NM_148923.4 missense, splice_region
Scores
2
15
2
Splicing: ADA: 0.9981
1
1
Clinical Significance
Conservation
PhyloP100: 4.36
Genes affected
CYB5A (HGNC:2570): (cytochrome b5 type A) The protein encoded by this gene is a membrane-bound cytochrome that reduces ferric hemoglobin (methemoglobin) to ferrous hemoglobin, which is required for stearyl-CoA-desaturase activity. Defects in this gene are a cause of type IV hereditary methemoglobinemia. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jun 2010]
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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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYB5A | NM_148923.4 | c.256C>T | p.Pro86Ser | missense_variant, splice_region_variant | 2/5 | ENST00000340533.9 | |
CYB5A | NM_001190807.3 | c.256C>T | p.Pro86Ser | missense_variant, splice_region_variant | 2/4 | ||
CYB5A | NM_001914.4 | c.256C>T | p.Pro86Ser | missense_variant, splice_region_variant | 2/6 | ||
CYB5A | XM_011525835.3 | c.256C>T | p.Pro86Ser | missense_variant, splice_region_variant | 2/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYB5A | ENST00000340533.9 | c.256C>T | p.Pro86Ser | missense_variant, splice_region_variant | 2/5 | 1 | NM_148923.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152100Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251264Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135788
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461738Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727166
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74302
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 17, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 30, 2022 | The c.256C>T (p.P86S) alteration is located in exon 2 (coding exon 2) of the CYB5A gene. This alteration results from a C to T substitution at nucleotide position 256, causing the proline (P) at amino acid position 86 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;T
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;.;M;M
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;D;D
REVEL
Uncertain
Sift
Uncertain
D;.;T;T
Sift4G
Uncertain
D;D;T;T
Polyphen
P;.;D;.
Vest4
MutPred
Gain of phosphorylation at P86 (P = 0.0417);.;Gain of phosphorylation at P86 (P = 0.0417);Gain of phosphorylation at P86 (P = 0.0417);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at