chr17-63436148-C-T

Variant names:

• chr17-63436148-C-T
• rs35447397
• NM_001915.4:c.207G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_001915.4(CYB561):​c.207G>A​(p.Leu69Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,613,808 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0071 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00069 (14 hom.)
• Consequence: CYB561 NM_001915.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.988
• Publications: 1 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 17-63436148-C-T is Benign according to our data. Variant chr17-63436148-C-T is described in ClinVar as Benign. ClinVar VariationId is 3034465.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=0.988 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00706 (1075/152318) while in subpopulation AFR AF = 0.0245 (1020/41572). AF 95% confidence interval is 0.0233. There are 14 homozygotes in GnomAd4. There are 501 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

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.207G>A	p.Leu69Leu	synonymous	Exon 3 of 6	NP_001906.3
	CYB561	NM_001330421.2		c.228G>A	p.Leu76Leu	synonymous	Exon 3 of 6	NP_001317350.1	J3QRH5
	CYB561	NM_001017916.2		c.207G>A	p.Leu69Leu	synonymous	Exon 3 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.207G>A	p.Leu69Leu	synonymous	Exon 3 of 6	ENSP00000354028.3	P49447-1
	CYB561	ENST00000580691.5	TSL:1	c.366G>A	p.Leu122Leu	synonymous	Exon 3 of 6	ENSP00000462545.1	J3KSL5
	CYB561	ENST00000392975.6	TSL:1	c.207G>A	p.Leu69Leu	synonymous	Exon 3 of 6	ENSP00000376701.2	P49447-1

Frequencies

GnomAD3 genomes AF: 0.00704 AC: 1071 AN: 152200 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00180 AC: 451 AN: 250672 AF XY: 0.00149

Gnomad AFR exome AF: 0.0245

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.000686 AC: 1002 AN: 1461490 Hom.: 14 Cov.: 32 AF XY: 0.000612 AC XY: 445 AN XY: 727036

African (AFR) AF: 0.0249 AC: 834 AN: 33472

American (AMR) AF: 0.00141 AC: 63 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111712

Other (OTH) AF: 0.00157 AC: 95 AN: 60374

GnomAD4 genome AF: 0.00706 AC: 1075 AN: 152318 Hom.: 14 Cov.: 33 AF XY: 0.00673 AC XY: 501 AN XY: 74486

African (AFR) AF: 0.0245 AC: 1020 AN: 41572

American (AMR) AF: 0.00268 AC: 41 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68002

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00339 Hom.: 10

Bravo AF: 0.00772

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CYB561-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	15
DANN	Benign	0.79
PhyloP100		0.99
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs35447397; hg19: chr17-61513509;