chr17-4149972-C-A

Variant names:

• chr17-4149972-C-A
• rs780587456
• NM_144611.4:c.332C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001254755.2(CYB5D2):​c.-5C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,010 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: CYB5D2 NM_001254755.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56
• 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06286177).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001254755.2. 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.332C>A	p.Ala111Asp	missense	Exon 2 of 4	NP_653212.1	Q8WUJ1-1
	CYB5D2	NM_001254755.2		c.-5C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	NP_001241684.1	Q8WUJ1-3
	CYB5D2	NM_001254756.1		c.-5C>A		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.332C>A	p.Ala111Asp	missense	Exon 2 of 4	ENSP00000301391.4	Q8WUJ1-1
	CYB5D2	ENST00000575251.5	TSL:2	c.-5C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000458903.1	Q8WUJ1-3
	CYB5D2	ENST00000577075.6	TSL:2	c.-5C>A		5_prime_UTR_premature_start_codon_gain	Exon 2 of 4	ENSP00000458352.2	Q8WUJ1-3

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000437 AC: 11 AN: 251492 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.000291 AC: 13 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000490167), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74302

African (AFR) AF: 0.00 AC: 0 AN: 41428

American (AMR) AF: 0.0000655 AC: 1 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

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	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	18
DANN	Benign	0.60
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.0079	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.31	N
PhyloP100		1.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.36	N
REVEL	Benign	0.16
Sift	Benign	0.61	T
Sift4G	Benign	0.59	T
Polyphen		0.0050	B
Vest4		0.34
MutPred		0.40		Gain of disorder (P = 0.0401)
MVP		0.24
MPC		0.21
ClinPred		0.031	T
GERP RS		4.4
Varity_R		0.14
gMVP		0.63

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: rs780587456; hg19: chr17-4053266;