dbSNP rs140451650: CEP63:p.Arg444Gln (chr3-134550211-G-A) – ACMG Classification: Benign (-20 pts)

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.1331G>A(p.Arg444Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000648 in 1,614,102 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00068 ( 3 hom. )

Consequence

CEP63
NM_001353108.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.585

Publications

4 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: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
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=0.0036670864).

BP6

Variant 3-134550211-G-A is Benign according to our data. Variant chr3-134550211-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 434748.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000677 (990/1461812) while in subpopulation AMR AF = 0.00304 (136/44724). AF 95% confidence interval is 0.00262. There are 3 homozygotes in GnomAdExome4. There are 452 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 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	UniProt
CEP63	NM_001353108.3	MANE Select	c.1331G>A	p.Arg444Gln	missense	Exon 11 of 15	NP_001340037.1	Q96MT8-1
CEP63	NM_025180.5		c.1331G>A	p.Arg444Gln	missense	Exon 12 of 16	NP_079456.2
CEP63	NM_001353109.1		c.1193G>A	p.Arg398Gln	missense	Exon 10 of 14	NP_001340038.1	A0A804HIX3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CEP63	ENST00000675561.1	MANE Select	c.1331G>A	p.Arg444Gln	missense	Exon 11 of 15	ENSP00000502085.1	Q96MT8-1
CEP63	ENST00000383229.8	TSL:1	c.1331G>A	p.Arg444Gln	missense	Exon 11 of 13	ENSP00000372716.3	Q96MT8-2
CEP63	ENST00000332047.10	TSL:1	c.1193G>A	p.Arg398Gln	missense	Exon 10 of 12	ENSP00000328382.5	Q96MT8-3

Frequencies

GnomAD3 genomes

AF:

0.000368

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.000603

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000806

AC:

202

AN:

250760

AF XY:

0.000649

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00330

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000424

Gnomad OTH exome

AF:

0.00507

GnomAD4 exome

AF:

0.000677

AC:

990

AN:

1461812

Hom.:

Cov.:

AF XY:

0.000622

AC XY:

452

AN XY:

727208

show subpopulations

African (AFR)

AF:

0.000179

AC:

AN:

33480

American (AMR)

AF:

0.00304

AC:

136

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39682

South Asian (SAS)

AF:

0.000197

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000719

AC:

800

AN:

1111972

Other (OTH)

AF:

0.000497

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

146

195

244

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000368

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41556

American (AMR)

AF:

0.000850

AC:

AN:

15300

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:

10596

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

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:

0.000496

Hom.:

Bravo

AF:

0.000627

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.000815

AC:

EpiCase

AF:

0.000600

EpiControl

AF:

0.000533

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

CEP63-related disorder (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.69

CADD

Benign

(source)

DANN

Benign

0.64

DEOGEN2

Benign

0.011

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.88

FATHMM_MKL

Benign

0.033

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.0038

MetaRNN

Benign

0.0037

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.090

PhyloP100

0.58

PrimateAI

Benign

0.18

PROVEAN

Benign

1.3

REVEL

Benign

0.028

Sift

Benign

1.0

Sift4G

Benign

0.41

Polyphen

0.0050

Vest4

0.14

MVP

0.27

MPC

0.031

ClinPred

0.0045

GERP RS

0.18

Varity_R

0.020

gMVP

0.071

Mutation Taster

=100/0

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

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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

Computational scores

Splicing

Publications

Other links and lift over