rs114108011

chr3-134537268-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 4P and 16B. PP3_Strong BP6_Very_Strong BS1 BS2

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 (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (53 hom., cov: 32)
  • Exomes 𝑓: 0.021 (518 hom.)
• Consequence: CEP63 NM_001353108.3 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.68

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: 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: 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: High Homozygotes in GnomAd at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP63	NM_001353108.3	c.555G>C	p.Gln185His	missense_variant, splice_region_variant	6/15	ENST00000675561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP63	ENST00000675561.1	c.555G>C	p.Gln185His	missense_variant, splice_region_variant	6/15		NM_001353108.3	A1

Frequencies

GnomAD3 genomes AF: 0.0201 AC: 3058 AN: 152164 Hom.: 53 Cov.: 32

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.0837

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0256

Gnomad OTH AF: 0.0138

GnomAD3 exomes AF: 0.0213 AC: 5348 AN: 251168 Hom.: 130 AF XY: 0.0213 AC XY: 2895 AN XY: 135742

Gnomad AFR exome AF: 0.00308

Gnomad AMR exome AF: 0.00547

Gnomad ASJ exome AF: 0.0109

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00281

Gnomad FIN exome AF: 0.0865

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0215

GnomAD4 exome AF: 0.0209 AC: 29918 AN: 1431232 Hom.: 518 Cov.: 24 AF XY: 0.0204 AC XY: 14577 AN XY: 713974

Gnomad4 AFR exome AF: 0.00289

Gnomad4 AMR exome AF: 0.00604

Gnomad4 ASJ exome AF: 0.0102

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.00286

Gnomad4 FIN exome AF: 0.0851

Gnomad4 NFE exome AF: 0.0215

Gnomad4 OTH exome AF: 0.0189

GnomAD4 genome AF: 0.0201 AC: 3055 AN: 152282 Hom.: 53 Cov.: 32 AF XY: 0.0219 AC XY: 1628 AN XY: 74452

Gnomad4 AFR AF: 0.00363

Gnomad4 AMR AF: 0.0108

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.0837

Gnomad4 NFE AF: 0.0256

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.0211 Hom.: 44

Bravo AF: 0.0135

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0186 AC: 160

ExAC AF: 0.0219 AC: 2657

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0208

EpiControl AF: 0.0187

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 07, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Pathogenic	32
Dann	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.83	T;.;T;T;.;.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.0041	T;T;T;T;T;T;T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.8	D;D;.;D;D;.;D
REVEL	Benign	0.28
Sift	Uncertain	0.024	D;D;.;D;D;.;D
Sift4G	Uncertain	0.033	D;D;D;D;D;D;D
Polyphen		1.0	D;D;D;D;P;P;P
Vest4		0.82
MutPred		0.32		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);
MPC		0.22
ClinPred		0.014	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.48

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs114108011; hg19: chr3-134256110;