rs766435188

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM4_SupportingPP3_ModerateBS1_Supporting

The NM_001353108.3(CEP63):c.1381_1383delGAG(p.Glu461del) variant causes a conservative inframe deletion, splice region change. The variant allele was found at a frequency of 0.0000638 in 1,597,794 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

CEP63
NM_001353108.3 conservative_inframe_deletion, splice_region

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.30

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001353108.3. Strenght limited to Supporting due to length of the change: 1aa.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000357 (54/151442) while in subpopulation AFR AF = 0.00116 (48/41350). AF 95% confidence interval is 0.000899. There are 0 homozygotes in GnomAd4. There are 32 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1381_1383delGAG	p.Glu461del	conservative_inframe_deletion splice_region	Exon 12 of 15	NP_001340037.1
CEP63	NM_025180.5		c.1381_1383delGAG	p.Glu461del	conservative_inframe_deletion splice_region	Exon 13 of 16	NP_079456.2
CEP63	NM_001353109.1		c.1243_1245delGAG	p.Glu415del	conservative_inframe_deletion splice_region	Exon 11 of 14	NP_001340038.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEP63	ENST00000675561.1	MANE Select	c.1381-2_1381delAGG	p.Glu461fs	frameshift splice_acceptor splice_region intron	Exon 12 of 15	ENSP00000502085.1
CEP63	ENST00000383229.8	TSL:1	c.1381-2_1381delAGG	p.Glu461fs	frameshift splice_acceptor splice_region intron	Exon 12 of 13	ENSP00000372716.3
CEP63	ENST00000332047.10	TSL:1	c.1243-2_1243delAGG	p.Glu415fs	frameshift splice_acceptor splice_region intron	Exon 11 of 12	ENSP00000328382.5

Frequencies

GnomAD3 genomes

AF:

0.000357

AC:

AN:

151338

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000395

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000966

AC:

AN:

248412

AF XY:

0.0000670

show subpopulations

Gnomad AFR exome

AF:

0.00125

Gnomad AMR exome

AF:

0.0000883

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000332

AC:

AN:

1446352

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

720148

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

33118

American (AMR)

AF:

0.0000906

AC:

AN:

44136

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25860

East Asian (EAS)

AF:

0.00

AC:

AN:

39356

South Asian (SAS)

AF:

0.00

AC:

AN:

84580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52884

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

9.08e-7

AC:

AN:

1100900

Other (OTH)

AF:

0.000134

AC:

AN:

59818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000357

AC:

AN:

151442

Hom.:

Cov.:

AF XY:

0.000432

AC XY:

AN XY:

73994

show subpopulations

African (AFR)

AF:

0.00116

AC:

AN:

41350

American (AMR)

AF:

0.000394

AC:

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67858

Other (OTH)

AF:

0.00

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000285

Hom.:

Bravo

AF:

0.000366

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 23, 2015

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Uncertain:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant, c.1381_1383del, results in the deletion of 1 amino acid(s) of the CEP63 protein (p.Glu461del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766435188, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CEP63-related conditions. ClinVar contains an entry for this variant (Variation ID: 434754). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.88

Position offset: 6

DS_AL_spliceai

1.0

Position offset: 3

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over