rs200994552
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting
The NM_001353108.3(CEP63):c.5A>T(p.Glu2Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000403 in 1,613,682 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000036 ( 1 hom. )
Consequence
CEP63
NM_001353108.3 missense
NM_001353108.3 missense
Scores
2
7
8
Clinical Significance
Conservation
PhyloP100: 4.32
Genes affected
CEP63 (HGNC:25815): (centrosomal protein 63) This gene encodes a protein with six coiled-coil domains. The protein is localized to the centrosome, a non-membraneous organelle that functions as the major microtubule-organizing center in animal cells. Several alternatively spliced transcript variants have been found, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.03486532).
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000854 (13/152310) while in subpopulation EAS AF= 0.00193 (10/5192). AF 95% confidence interval is 0.00104. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CEP63 | NM_001353108.3 | c.5A>T | p.Glu2Val | missense_variant | 2/15 | ENST00000675561.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CEP63 | ENST00000675561.1 | c.5A>T | p.Glu2Val | missense_variant | 2/15 | NM_001353108.3 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152192Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000151 AC: 38AN: 251432Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135882
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GnomAD4 exome AF: 0.0000356 AC: 52AN: 1461372Hom.: 1 Cov.: 30 AF XY: 0.0000440 AC XY: 32AN XY: 726988
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GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74486
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 128711). This variant has not been reported in the literature in individuals affected with CEP63-related conditions. This variant is present in population databases (rs200994552, gnomAD 0.2%). This sequence change replaces glutamic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 2 of the CEP63 protein (p.Glu2Val). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Dec 06, 2013 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 19, 2022 | The c.5A>T (p.E2V) alteration is located in exon 3 (coding exon 1) of the CEP63 gene. This alteration results from a A to T substitution at nucleotide position 5, causing the glutamic acid (E) at amino acid position 2 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.;D;D;D;D;.;.;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;.;N;N;N;.;N
REVEL
Benign
Sift
Uncertain
D;D;D;.;D;D;D;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D
Polyphen
P;D;.;D;D;.;D;D;D
Vest4
MVP
MPC
0.22
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at