chr3-50353431-G-T

Position:

• chr3-50353431-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001291284.2(CYB561D2):​c.356G>T​(p.Arg119Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,624 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R119W) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYB561D2 NM_001291284.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.83

Genes affected

CYB561D2 (HGNC:30253): (cytochrome b561 family member D2) Enables heme binding activity and transmembrane monodehydroascorbate reductase activity. Involved in ascorbate homeostasis. Predicted to be located in vesicle. Predicted to be active in endoplasmic reticulum. [provided by Alliance of Genome Resources, Apr 2022]

LOC127898564 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYB561D2	NM_001291284.2	c.356G>T	p.Arg119Leu	missense_variant	4/4	ENST00000425346.6
LOC127898564	NR_183066.1	n.275+1871G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYB561D2	ENST00000425346.6	c.356G>T	p.Arg119Leu	missense_variant	4/4	1	NM_001291284.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460624 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726588

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000194 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 16, 2023

The c.356G>T (p.R119L) alteration is located in exon 4 (coding exon 3) of the CYB561D2 gene. This alteration results from a G to T substitution at nucleotide position 356, causing the arginine (R) at amino acid position 119 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.070	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.049	T;T;T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	0.070
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.43	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.5	N;N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.45	T
PROVEAN	Benign	1.0	N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.0030	B;B;B;B
Vest4		0.48
MutPred		0.68		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);
MVP		0.55
MPC		0.35
ClinPred		0.95	D
GERP RS		5.6
Varity_R		0.40
gMVP		0.43

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: rs748339296; hg19: chr3-50390862;