17-63440208-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001915.4(CYB561):c.-13-2648G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 398,780 control chromosomes in the GnomAD database, including 127 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (56 hom., cov: 32)
  • Exomes 𝑓: 0.023 (71 hom.)
• Consequence: CYB561 NM_001915.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.376

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 17-63440208-C-T is Benign according to our data. Variant chr17-63440208-C-T is described in ClinVar as [Benign]. Clinvar id is 3056754.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0192 (2917/152254) while in subpopulation NFE AF= 0.0304 (2068/68010). AF 95% confidence interval is 0.0293. There are 56 homozygotes in gnomad4. There are 1352 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 56 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB561	NM_001915.4	c.-13-2648G>A		intron_variant		ENST00000360793.8
CYB561	NM_001330421.2	c.-9G>A		5_prime_UTR_variant	1/6
CYB561	NM_001017916.2	c.-13-2648G>A		intron_variant
CYB561	NM_001017917.2	c.-14+519G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB561	ENST00000360793.8	c.-13-2648G>A		intron_variant		1	NM_001915.4	P1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2919 AN: 152136 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.00534

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0248

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.0223 AC: 7 AN: 314 Hom.: 0 AF XY: 0.0128 AC XY: 1 AN XY: 78

Gnomad AFR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.0275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0233 AC: 5751 AN: 246526 Hom.: 71 Cov.: 0 AF XY: 0.0232 AC XY: 2899 AN XY: 124962

Gnomad4 AFR exome AF: 0.00501

Gnomad4 AMR exome AF: 0.00874

Gnomad4 ASJ exome AF: 0.0260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0155

Gnomad4 FIN exome AF: 0.0251

Gnomad4 NFE exome AF: 0.0283

Gnomad4 OTH exome AF: 0.0190

GnomAD4 genome AF: 0.0192 AC: 2917 AN: 152254 Hom.: 56 Cov.: 32 AF XY: 0.0182 AC XY: 1352 AN XY: 74438

Gnomad4 AFR AF: 0.00532

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.0245

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.0248

Gnomad4 NFE AF: 0.0304

Gnomad4 OTH AF: 0.0156

Alfa AF: 0.0255 Hom.: 11

Bravo AF: 0.0170

Asia WGS AF: 0.0110 AC: 40 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

CYB561-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2019

This variant is classified as 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	-0.87
Cadd	Benign	5.5
Dann	Benign	0.46

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

Other links and lift over

dbSNP: rs72845004; hg19: chr17-61517569;