Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 1.27

Publications

7 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 -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 VariationId is 128707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353108.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEP63	NM_001353108.3	MANE Select	c.1155C>A	p.Asn385Lys	missense	Exon 10 of 15	NP_001340037.1
CEP63	NM_025180.5		c.1155C>A	p.Asn385Lys	missense	Exon 11 of 16	NP_079456.2
CEP63	NM_001353109.1		c.1017C>A	p.Asn339Lys	missense	Exon 9 of 14	NP_001340038.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEP63	ENST00000675561.1	MANE Select	c.1155C>A	p.Asn385Lys	missense	Exon 10 of 15	ENSP00000502085.1
CEP63	ENST00000383229.8	TSL:1	c.1155C>A	p.Asn385Lys	missense	Exon 10 of 13	ENSP00000372716.3
CEP63	ENST00000332047.10	TSL:1	c.1017C>A	p.Asn339Lys	missense	Exon 9 of 12	ENSP00000328382.5

Frequencies

GnomAD3 genomes

AF:

0.00685

AC:

1042

AN:

152066

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00217

AC:

545

AN:

250994

AF XY:

0.00170

show subpopulations

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 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.:

Cov.:

AF XY:

0.000581

AC XY:

422

AN XY:

725734

show subpopulations

African (AFR)

AF:

0.0226

AC:

756

AN:

33378

American (AMR)

AF:

0.00291

AC:

130

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39616

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86188

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00139

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.0000541

AC:

AN:

1108782

Other (OTH)

AF:

0.00168

AC:

101

AN:

60256

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

103

154

206

257

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00685

AC:

1043

AN:

152184

Hom.:

Cov.:

AF XY:

0.00656

AC XY:

488

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0230

AC:

953

AN:

41516

American (AMR)

AF:

0.00438

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10582

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

67998

Other (OTH)

AF:

0.00710

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00246

Hom.:

Bravo

AF:

0.00863

ESP6500AA

AF:

0.0250

AC:

110

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00256

AC:

311

Asia WGS

AF:

0.000578

AC:

AN:

3476

EpiCase

AF:

0.000273

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.42

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.041

Eigen

Benign

0.049

Eigen_PC

Benign

0.087

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.92

MetaRNN

Benign

0.0047

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

1.3

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.6

REVEL

Benign

0.044

Sift

Benign

0.47

Sift4G

Benign

1.0

Polyphen

0.082

Vest4

0.41

MutPred

0.28

Gain of ubiquitination at N385 (P = 0.0109)

MVP

0.56

MPC

0.095

ClinPred

0.025

GERP RS

3.0

Varity_R

0.068

gMVP

0.18

Mutation Taster

=97/3

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs34189216

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over