chr17-63436093-C-A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_001915.4(CYB561):​c.262G>T​(p.Gly88Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. G88R) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CYB561
NM_001915.4 missense

Scores

2
13
4

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.86

Publications

2 publications found
Variant links:
Genes affected
CYB561 (HGNC:2571): (cytochrome b561) Predicted to enable transmembrane monodehydroascorbate reductase activity. Predicted to be involved in ascorbate homeostasis. Predicted to be located in chromaffin granule membrane. Predicted to be active in lysosomal membrane. [provided by Alliance of Genome Resources, Apr 2022]
CYB561 Gene-Disease associations (from GenCC):
  • orthostatic hypotension 2
    Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-63436093-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 590763.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.853

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYB561NM_001915.4 linkc.262G>T p.Gly88Trp missense_variant Exon 3 of 6 ENST00000360793.8 NP_001906.3 P49447-1
CYB561NM_001330421.2 linkc.283G>T p.Gly95Trp missense_variant Exon 3 of 6 NP_001317350.1 P49447J3QRH5
CYB561NM_001017916.2 linkc.262G>T p.Gly88Trp missense_variant Exon 3 of 6 NP_001017916.1 P49447-1B3KTA1
CYB561NM_001017917.2 linkc.262G>T p.Gly88Trp missense_variant Exon 3 of 6 NP_001017917.1 P49447-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYB561ENST00000360793.8 linkc.262G>T p.Gly88Trp missense_variant Exon 3 of 6 1 NM_001915.4 ENSP00000354028.3 P49447-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD2 exomes
AF:
0.00000398
AC:
1
AN:
251270
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461868
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727238
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44722
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86258
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111994
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.375
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Uncertain
0.059
T
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
27
DANN
Benign
0.80
DEOGEN2
Benign
0.24
T;T;.;T;.;T;.;T;T;.;T;.
Eigen
Uncertain
0.55
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.92
.;.;D;D;D;.;D;D;D;D;.;D
M_CAP
Uncertain
0.17
D
MetaRNN
Pathogenic
0.85
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.64
T
MutationAssessor
Uncertain
2.7
M;M;.;M;.;M;M;.;.;.;M;.
PhyloP100
4.9
PrimateAI
Uncertain
0.54
T
PROVEAN
Uncertain
-4.3
D;D;.;D;.;.;D;.;D;.;.;.
REVEL
Uncertain
0.43
Sift
Uncertain
0.0010
D;D;.;D;.;.;D;.;D;.;.;.
Sift4G
Uncertain
0.017
D;D;D;D;D;D;D;D;D;D;.;.
Polyphen
1.0
D;D;.;D;.;D;.;.;D;.;D;.
Vest4
0.62
MutPred
0.72
.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0307);.;.;.;
MVP
0.18
MPC
1.1
ClinPred
0.99
D
GERP RS
4.9
Varity_R
0.67
gMVP
0.72

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

Other links and lift over

dbSNP: rs772361572; hg19: chr17-61513454; COSMIC: COSV62539733; COSMIC: COSV62539733; API