22-42649637-C-G

Position:

• chr22-42649637-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000692152.1(CYB5R3):​c.-48-12791G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.138 in 152,378 control chromosomes in the GnomAD database, including 2,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (2037 hom., cov: 32)
  • Exomes 𝑓: 0.13 (2 hom.)
• Consequence: CYB5R3 ENST00000692152.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0790

Genes affected

CYB5R3 (HGNC:2873): (cytochrome b5 reductase 3) This gene encodes cytochrome b5 reductase, which includes a membrane-bound form in somatic cells (anchored in the endoplasmic reticulum, mitochondrial and other membranes) and a soluble form in erythrocytes. The membrane-bound form exists mainly on the cytoplasmic side of the endoplasmic reticulum and functions in desaturation and elongation of fatty acids, in cholesterol biosynthesis, and in drug metabolism. The erythrocyte form is located in a soluble fraction of circulating erythrocytes and is involved in methemoglobin reduction. The membrane-bound form has both membrane-binding and catalytic domains, while the soluble form has only the catalytic domain. Alternate splicing results in multiple transcript variants. Mutations in this gene cause methemoglobinemias. [provided by RefSeq, Jan 2010]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 22-42649637-C-G is Benign according to our data. Variant chr22-42649637-C-G is described in ClinVar as [Benign]. Clinvar id is 1287070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB5R3	ENST00000686129.1	c.-48-12791G>C		intron_variant
CYB5R3	ENST00000692152.1	c.-48-12791G>C		intron_variant
CYB5R3	ENST00000693716.1	n.250-12791G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20929 AN: 152030 Hom.: 2039 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.0987

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.0816

Gnomad EAS AF: 0.580

Gnomad SAS AF: 0.228

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.143

GnomAD4 exome AF: 0.126 AC: 29 AN: 230 Hom.: 2 AF XY: 0.156 AC XY: 25 AN XY: 160

Gnomad4 AMR exome AF: 0.100

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.00

Gnomad4 NFE exome AF: 0.131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.138 AC: 20946 AN: 152148 Hom.: 2037 Cov.: 32 AF XY: 0.143 AC XY: 10648 AN XY: 74360

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.111

Gnomad4 ASJ AF: 0.0816

Gnomad4 EAS AF: 0.579

Gnomad4 SAS AF: 0.228

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.141

Alfa AF: 0.0702 Hom.: 79

Bravo AF: 0.134

Asia WGS AF: 0.348 AC: 1208 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	7.7
DANN	Benign	0.53

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28365958; hg19: chr22-43045643;