17-63436093-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PS1 PM2

The NM_001915.4(CYB561):c.262G>C(p.Gly88Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,614,214 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000046 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: CYB561 NM_001915.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.86

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 Likely_pathogenic. Variant got 6 ACMG points.

• PS1: Transcript NM_001915.4 (CYB561) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 590763
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB561	NM_001915.4	c.262G>C	p.Gly88Arg	missense_variant	3/6	ENST00000360793.8
CYB561	NM_001330421.2	c.283G>C	p.Gly95Arg	missense_variant	3/6
CYB561	NM_001017916.2	c.262G>C	p.Gly88Arg	missense_variant	3/6
CYB561	NM_001017917.2	c.262G>C	p.Gly88Arg	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB561	ENST00000360793.8	c.262G>C	p.Gly88Arg	missense_variant	3/6	1	NM_001915.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000438 AC: 11 AN: 251270 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135842

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000219 AC: 32 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000412

Gnomad4 NFE exome AF: 0.00000629

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000459 AC: 7 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.0000671 AC XY: 5 AN XY: 74498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000577 AC: 7

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	26
Dann	Benign	0.89
DEOGEN2	Benign	0.23	T;T;.;T;.;T;.;T;T;.;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.052	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.7	M;M;.;M;.;M;M;.;.;.;M;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.2	D;D;.;D;.;.;D;.;D;.;.;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.0030	D;D;.;D;.;.;D;.;D;.;.;.
Sift4G	Uncertain	0.030	D;D;D;D;T;D;D;D;D;D;.;.
Polyphen		1.0	D;D;.;D;.;D;.;.;D;.;D;.
Vest4		0.73
MutPred		0.74		.;.;.;.;.;.;.;.;Gain of MoRF binding (P = 0.0086);.;.;.;
MVP		0.33
MPC		1.1
ClinPred		0.87	D
GERP RS		4.9
Varity_R		0.55
gMVP		0.77

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: rs772361572; hg19: chr17-61513454;