Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PP3_StrongBP6_Very_StrongBS1BS2
The NM_001353108.3(CEP63):c.555G>C(p.Gln185His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0208 in 1,583,514 control chromosomes in the GnomAD database, including 571 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★).
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]
PP3 - Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 3-134537268-G-C is Benign according to our data. Variant chr3-134537268-G-C is described in ClinVar as [Benign]. Clinvar id is 128709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-134537268-G-C is described in Lovd as [Likely_benign].
BS1
?
BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0201 (3055/152282) while in subpopulation NFE AF= 0.0256 (1744/68024). AF 95% confidence interval is 0.0246. There are 53 homozygotes in gnomad4. There are 1628 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
Gain of catalytic residue at I183 (P = 0.1009);Gain of catalytic residue at I183 (P = 0.1009);Gain of catalytic residue at I183 (P = 0.1009);Gain of catalytic residue at I183 (P = 0.1009);Gain of catalytic residue at I183 (P = 0.1009);Gain of catalytic residue at I183 (P = 0.1009);Gain of catalytic residue at I183 (P = 0.1009);