rs34189216

Positions:

• chr3-134549149-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001353108.3(CEP63):​c.1155C>A​(p.Asn385Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,610,376 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N385T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0069 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00073 (11 hom.)
• Consequence: CEP63 NM_001353108.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.27

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047411025).
• BP6: Variant 3-134549149-C-A is Benign according to our data. Variant chr3-134549149-C-A is described in ClinVar as [Benign]. Clinvar id is 128707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-134549149-C-A is described in Lovd as [Benign]. Variant chr3-134549149-C-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00685 (1043/152184) while in subpopulation AFR AF= 0.023 (953/41516). AF 95% confidence interval is 0.0217. There are 7 homozygotes in gnomad4. There are 488 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP63	NM_001353108.3	c.1155C>A	p.Asn385Lys	missense_variant	10/15	ENST00000675561.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP63	ENST00000675561.1	c.1155C>A	p.Asn385Lys	missense_variant	10/15		NM_001353108.3	A1

Frequencies

GnomAD3 genomes AF: 0.00685 AC: 1042 AN: 152066 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00439

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: 0.000118

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00217 AC: 545 AN: 250994 Hom.: 6 AF XY: 0.00170 AC XY: 231 AN XY: 135648

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000882

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.000726 AC: 1058 AN: 1458192 Hom.: 11 Cov.: 29 AF XY: 0.000581 AC XY: 422 AN XY: 725734

Gnomad4 AFR exome AF: 0.0226

Gnomad4 AMR exome AF: 0.00291

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: 0.0000541

Gnomad4 OTH exome AF: 0.00168

GnomAD4 genome AF: 0.00685 AC: 1043 AN: 152184 Hom.: 7 Cov.: 32 AF XY: 0.00656 AC XY: 488 AN XY: 74390

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00710

Alfa AF: 0.00135 Hom.: 1

Bravo AF: 0.00863

ESP6500AA AF: 0.0250 AC: 110

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00256 AC: 311

Asia WGS AF: 0.000578 AC: 2 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 16, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.42
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	22
DANN	Uncertain	0.99
Eigen	Benign	0.049
Eigen_PC	Benign	0.087
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.92	D;.;D;D;.;.;D;D
MetaRNN	Benign	0.0047	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.89	N;N;N;N;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.6	N;N;.;N;N;.;N;N
REVEL	Benign	0.044
Sift	Benign	0.47	T;T;.;T;T;.;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T
Polyphen		0.082	B;P;P;P;D;D;D;.
Vest4		0.41
MutPred		0.28		.;.;.;Gain of ubiquitination at N385 (P = 0.0109);Gain of ubiquitination at N385 (P = 0.0109);Gain of ubiquitination at N385 (P = 0.0109);Gain of ubiquitination at N385 (P = 0.0109);.;
MVP		0.56
MPC		0.095
ClinPred		0.025	T
GERP RS		3.0
Varity_R		0.068
gMVP		0.18

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

Publications

LitVar

Other links and lift over

dbSNP: rs34189216; hg19: chr3-134267991;