17-63435774-C-T

Variant names:

• chr17-63435774-C-T
• rs766550269
• NM_001915.4:c.319G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001915.4(CYB561):​c.319G>A​(p.Asp107Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,614,026 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: CYB561 NM_001915.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01
• Publications: 2 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20289177).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001915.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB561	NM_001915.4	MANE Select	c.319G>A	p.Asp107Asn	missense	Exon 4 of 6	NP_001906.3
	CYB561	NM_001330421.2		c.340G>A	p.Asp114Asn	missense	Exon 4 of 6	NP_001317350.1	J3QRH5
	CYB561	NM_001017916.2		c.319G>A	p.Asp107Asn	missense	Exon 4 of 6	NP_001017916.1	P49447-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB561	ENST00000360793.8	TSL:1 MANE Select	c.319G>A	p.Asp107Asn	missense	Exon 4 of 6	ENSP00000354028.3	P49447-1
	CYB561	ENST00000580691.5	TSL:1	c.478G>A	p.Asp160Asn	missense	Exon 4 of 6	ENSP00000462545.1	J3KSL5
	CYB561	ENST00000392975.6	TSL:1	c.319G>A	p.Asp107Asn	missense	Exon 4 of 6	ENSP00000376701.2	P49447-1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000597 AC: 15 AN: 251414 AF XY: 0.0000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000944 AC: 138 AN: 1461834 Hom.: 0 Cov.: 31 AF XY: 0.0000866 AC XY: 63 AN XY: 727214

African (AFR) AF: 0.000119 AC: 4 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000115 AC: 128 AN: 1111976

Other (OTH) AF: 0.0000662 AC: 4 AN: 60396

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152192 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74342

African (AFR) AF: 0.000169 AC: 7 AN: 41448

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.025	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		2.0
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.067
Sift	Benign	0.040	D
Sift4G	Benign	0.15	T
Polyphen		0.12	B
Vest4		0.29
MVP		0.15
MPC		0.31
ClinPred		0.099	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.15
gMVP		0.21
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs766550269; hg19: chr17-61513135;