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GeneBe

17-63435088-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2BP4_StrongBP6_ModerateBP7

The NM_001915.4(CYB561):c.561C>T(p.Leu187=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00037 in 1,612,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00032 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00038 ( 0 hom. )

Consequence

CYB561
NM_001915.4 splice_region, synonymous

Scores

2
Splicing: ADA: 0.0001860
2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.155
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM2
?
    PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.83).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-63435088-G-A is Benign according to our data. Variant chr17-63435088-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3046415.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=-0.155 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYB561NM_001915.4 linkuse as main transcriptc.561C>T p.Leu187= splice_region_variant, synonymous_variant 5/6 ENST00000360793.8
CYB561NM_001330421.2 linkuse as main transcriptc.582C>T p.Leu194= splice_region_variant, synonymous_variant 5/6
CYB561NM_001017916.2 linkuse as main transcriptc.561C>T p.Leu187= splice_region_variant, synonymous_variant 5/6
CYB561NM_001017917.2 linkuse as main transcriptc.561C>T p.Leu187= splice_region_variant, synonymous_variant 5/6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYB561ENST00000360793.8 linkuse as main transcriptc.561C>T p.Leu187= splice_region_variant, synonymous_variant 5/61 NM_001915.4 P1P49447-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000315
AC:
48
AN:
152244
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000523
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000544
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000340
AC:
85
AN:
249760
Hom.:
0
AF XY:
0.000318
AC XY:
43
AN XY:
135098
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.0000656
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000639
Gnomad OTH exome
AF:
0.000329
GnomAD4 exome
AF:
0.000376
AC:
549
AN:
1460628
Hom.:
0
Cov.:
32
AF XY:
0.000373
AC XY:
271
AN XY:
726594
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000269
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.0000564
Gnomad4 NFE exome
AF:
0.000454
Gnomad4 OTH exome
AF:
0.000414
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.000315
AC:
48
AN:
152362
Hom.:
0
Cov.:
33
AF XY:
0.000242
AC XY:
18
AN XY:
74500
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.000523
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000941
Gnomad4 NFE
AF:
0.000544
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000393
Hom.:
0
Bravo
AF:
0.000355
EpiCase
AF:
0.00104
EpiControl
AF:
0.000653

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

CYB561-related disorder Benign:1
Likely benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesApr 09, 2019This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.83
Cadd
Benign
0.021
Dann
Benign
0.60

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00019
dbscSNV1_RF
Benign
0.054
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: rs144041303; hg19: chr17-61512449; API