14-24306522-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001393339.1(CIDEB):c.188C>A(p.Ala63Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,886 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: CIDEB NM_001393339.1 missense, splice_region
• Scores: Splicing: ADA: 0.07075
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.33

Genes affected

CIDEB (HGNC:1977): (cell death inducing DFFA like effector b) Enables identical protein binding activity. Involved in activation of cysteine-type endopeptidase activity; positive regulation of cell death; and positive regulation of release of cytochrome c from mitochondria. Acts upstream of or within apoptotic process. Located in cytosol and perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NOP9 (HGNC:19826): (NOP9 nucleolar protein) Enables RNA binding activity. Predicted to be involved in ribosome biogenesis. Predicted to be part of 90S preribosome and preribosome, small subunit precursor. Predicted to be active in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

LTB4R2 (HGNC:19260): (leukotriene B4 receptor 2) Predicted to enable G protein-coupled peptide receptor activity and leukotriene B4 receptor activity. Predicted to be involved in inflammatory response and neuropeptide signaling pathway. Predicted to act upstream of or within keratinocyte migration and signal transduction. Located in nucleoplasm and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIDEB	NM_001393339.1	c.188C>A	p.Ala63Glu	missense_variant, splice_region_variant	3/5	ENST00000554411.6
NOP9	NM_174913.3	c.*1427G>T		3_prime_UTR_variant	10/10	ENST00000267425.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIDEB	ENST00000554411.6	c.188C>A	p.Ala63Glu	missense_variant, splice_region_variant	3/5	1	NM_001393339.1	P1
NOP9	ENST00000267425.8	c.*1427G>T		3_prime_UTR_variant	10/10	1	NM_174913.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251428 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135872

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727246

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

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

Aug 19, 2023

The c.188C>A (p.A63E) alteration is located in exon 5 (coding exon 3) of the CIDEB gene. This alteration results from a C to A substitution at nucleotide position 188, causing the alanine (A) at amino acid position 63 to be replaced by a glutamic acid (E). 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	Pathogenic	0.84
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.11
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.69	D;D;D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.0	M;M;M
MutationTaster	Benign	0.97	D;D;D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.014	D;D;D
Sift4G	Uncertain	0.033	D;D;D
Polyphen		0.89	P;P;P
Vest4		0.74
MutPred		0.81		Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);Gain of disorder (P = 0.0499);
MVP		0.69
MPC		0.68
ClinPred		0.94	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.071
dbscSNV1_RF	Benign	0.35
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: rs1459313856; hg19: chr14-24775728;