17-4143940-G-T

Variant names:

• chr17-4143940-G-T
• NM_144611.4:c.185G>T

Variant summary

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

The NM_144611.4(CYB5D2):​c.185G>T​(p.Arg62Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,164 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CYB5D2 NM_144611.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33

Genes affected

CYB5D2 (HGNC:28471): (cytochrome b5 domain containing 2) Predicted to enable heme binding activity. Predicted to be involved in nervous system development. Predicted to act upstream of or within positive regulation of neuron differentiation. Predicted to be located in extracellular region. Predicted to be active in endomembrane system and membrane. [provided by Alliance of Genome Resources, Apr 2022]

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 rank	MANE	Protein	UniProt
CYB5D2	NM_144611.4	c.185G>T	p.Arg62Leu	missense_variant	Exon 1 of 4	ENST00000301391.8	NP_653212.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYB5D2	ENST00000301391.8	c.185G>T	p.Arg62Leu	missense_variant	Exon 1 of 4	1	NM_144611.4	ENSP00000301391.4
CYB5D2	ENST00000575251.5	c.-87+177G>T		intron_variant	Intron 1 of 3	2		ENSP00000458903.1
CYB5D2	ENST00000577075.6	c.-87+627G>T		intron_variant	Intron 1 of 3	2		ENSP00000458352.2
CYB5D2	ENST00000573984.1	c.-87+177G>T		intron_variant	Intron 1 of 3	4		ENSP00000461090.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461164 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726886

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.185G>T (p.R62L) alteration is located in exon 1 (coding exon 1) of the CYB5D2 gene. This alteration results from a G to T substitution at nucleotide position 185, causing the arginine (R) at amino acid position 62 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	0.22
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.62	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.072	T
Polyphen		0.95	P
Vest4		0.58
MutPred		0.59		Loss of disorder (P = 0.0523);
MVP		0.55
MPC		0.31
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.59
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-4047234;