NM_144611.4:c.274G>C

Variant names:

• chr17-4149914-G-C
• rs772508937
• NM_144611.4:c.274G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_144611.4(CYB5D2):​c.274G>C​(p.Val92Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. V92M) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYB5D2 NM_144611.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.56
• Publications: 0 publications found

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]

ENSG00000308322 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144611.4. 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
	CYB5D2	NM_144611.4	MANE Select	c.274G>C	p.Val92Leu	missense	Exon 2 of 4	NP_653212.1	Q8WUJ1-1
	CYB5D2	NM_001254755.2		c.-63G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001241684.1	Q8WUJ1-3
	CYB5D2	NM_001254756.1		c.-63G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001241685.1	Q8WUJ1-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYB5D2	ENST00000301391.8	TSL:1 MANE Select	c.274G>C	p.Val92Leu	missense	Exon 2 of 4	ENSP00000301391.4	Q8WUJ1-1
	CYB5D2	ENST00000575251.5	TSL:2	c.-63G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000458903.1	Q8WUJ1-3
	CYB5D2	ENST00000577075.6	TSL:2	c.-63G>C		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000458352.2	Q8WUJ1-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		3.6
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.015	D
Sift4G	Uncertain	0.039	D
Polyphen		0.99	D
Vest4		0.50
MutPred		0.56		Gain of disorder (P = 0.2091)
MVP		0.24
MPC		0.51
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.24
gMVP		0.69

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

Other links and lift over

dbSNP: rs772508937; hg19: chr17-4053208;