3-134537268-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★).

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:4

Conservation

PhyloP100: 7.68

Publications

9 publications found

Variant links:

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]

CEP63 Gene-Disease associations (from GenCC):

Seckel syndrome 6
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal recessive primary microcephaly
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP63 links:

ENSG00000288700 (HGNC:):

ENSG00000288700 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP3

Splicing predictors support a deleterious 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 VariationId is 128709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 53 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP63	NM_001353108.3 link	c.555G>C	p.Gln185His	missense_variant, splice_region_variant	Exon 6 of 15	ENST00000675561.1	NP_001340037.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP63	ENST00000675561.1 link	c.555G>C	p.Gln185His	missense_variant, splice_region_variant	Exon 6 of 15		NM_001353108.3	ENSP00000502085.1		Q96MT8-1

Frequencies

GnomAD3 genomes

AF:

0.0201

AC:

3058

AN:

152164

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0213

AC:

5348

AN:

251168

AF XY:

0.0213

show subpopulations

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 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.:

AF XY:

0.0204

AC XY:

14577

AN XY:

713974

show subpopulations

African (AFR)

AF:

0.00289

AC:

AN:

32892

American (AMR)

AF:

0.00604

AC:

270

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.0102

AC:

264

AN:

25932

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39566

South Asian (SAS)

AF:

0.00286

AC:

245

AN:

85670

European-Finnish (FIN)

AF:

0.0851

AC:

4543

AN:

53368

Middle Eastern (MID)

AF:

0.00578

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.0215

AC:

23342

AN:

1084024

Other (OTH)

AF:

0.0189

AC:

1125

AN:

59388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

1396

2792

4188

5584

6980

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

768

1536

2304

3072

3840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0201

AC:

3055

AN:

152282

Hom.:

Cov.:

AF XY:

0.0219

AC XY:

1628

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00363

AC:

151

AN:

41550

American (AMR)

AF:

0.0108

AC:

166

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.00352

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0837

AC:

888

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0256

AC:

1744

AN:

68024

Other (OTH)

AF:

0.0132

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

149

298

448

597

746

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0211

Hom.:

Bravo

AF:

0.0135

TwinsUK

AF:

0.0173

AC:

ALSPAC

AF:

0.0158

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.0186

AC:

160

ExAC

AF:

0.0219

AC:

2657

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0208

EpiControl

AF:

0.0187

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

May 07, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

.;.;.;.;T;T;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.83

T;.;T;T;.;.;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.0041

T;T;T;T;T;T;T

MetaSVM

Benign

-0.73

MutationAssessor

Uncertain

2.0

M;M;M;M;M;M;M

PhyloP100

7.7

PrimateAI

Uncertain

0.57

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

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.62

gMVP

0.48

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over