Genetic Variant CEP78:p.Glu319Gln (chr9-78248353-G-C) – ACMG Classification: Benign (-15 pts)

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2

The NM_001330691.3(CEP78):c.955G>C(p.Glu319Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,555,972 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E319E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0089 ( 16 hom., cov: 32)

Exomes 𝑓: 0.00093 ( 15 hom. )

Consequence

CEP78
NM_001330691.3 missense, splice_region

Scores

Splicing: ADA: 0.9579

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.39

Publications

7 publications found

Variant links:

Genes affected

CEP78 (HGNC:25740): (centrosomal protein 78) This gene encodes a centrosomal protein that is both required for the regulation of centrosome-related events during the cell cycle, and required for ciliogenesis. The encoded protein has an N-terminal leucine-rich repeat (LRR) domain with six consecutive LRR repeats, and a C-terminal coiled-coil domain. It interacts with the N-terminal catalytic domain of polo-like kinase 4 (PLK4) and colocalizes with PLK4 to the distal end of the centriole. Naturally occurring mutations in this gene cause defects in primary cilia that result in retinal degeneration and sensorineural hearing loss which are associated with cone-rod degeneration disease as well as Usher syndrome. Low expression of this gene is associated with poor prognosis of colorectal cancer patients. [provided by RefSeq, Mar 2017]

CEP78 Gene-Disease associations (from GenCC):

cone-rod dystrophy and hearing loss
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, G2P
cone-rod dystrophy and hearing loss 1
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
Usher syndrome type 3
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP78 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -15 ACMG points.

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

BP6

Variant 9-78248353-G-C is Benign according to our data. Variant chr9-78248353-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 517540.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 = 0.00887 (1351/152232) while in subpopulation AFR AF = 0.0303 (1260/41542). AF 95% confidence interval is 0.0289. There are 16 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 16 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330691.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEP78	NM_001330691.3	MANE Select	c.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 17	NP_001317620.1
CEP78	NM_001098802.3		c.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 16	NP_001092272.1
CEP78	NM_001349838.2		c.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 16	NP_001336767.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CEP78	ENST00000643273.2	MANE Select	c.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 17	ENSP00000496423.2
CEP78	ENST00000376597.9	TSL:1	c.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 16	ENSP00000365782.4
CEP78	ENST00000643499.1		c.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 17	ENSP00000495962.1

Frequencies

GnomAD3 genomes

AF:

0.00880

AC:

1338

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00412

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00216

AC:

537

AN:

248466

AF XY:

0.00164

show subpopulations

Gnomad AFR exome

AF:

0.0294

Gnomad AMR exome

AF:

0.00177

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000978

Gnomad OTH exome

AF:

0.000996

GnomAD4 exome

AF:

0.000932

AC:

1308

AN:

1403740

Hom.:

Cov.:

AF XY:

0.000809

AC XY:

568

AN XY:

702118

show subpopulations

African (AFR)

AF:

0.0295

AC:

952

AN:

32220

American (AMR)

AF:

0.00226

AC:

101

AN:

44612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25732

East Asian (EAS)

AF:

0.00

AC:

AN:

39426

South Asian (SAS)

AF:

0.0000824

AC:

AN:

84974

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53348

Middle Eastern (MID)

AF:

0.00354

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.0000746

AC:

AN:

1059410

Other (OTH)

AF:

0.00255

AC:

149

AN:

58362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

112

168

224

280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00887

AC:

1351

AN:

152232

Hom.:

Cov.:

AF XY:

0.00825

AC XY:

614

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0303

AC:

1260

AN:

41542

American (AMR)

AF:

0.00412

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68006

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

127

191

254

318

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:

0.000454

Hom.:

Bravo

AF:

0.00992

ESP6500AA

AF:

0.0284

AC:

103

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00237

AC:

286

Asia WGS

AF:

0.00289

AC:

AN:

3478

EpiCase

AF:

0.000328

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Glu319Gln in exon 7 of CEP78: This variant is not expected to have clinical si gnificance because it has been identified in 2.84% (263/9252) of African chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs61730338).

Aug 18, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Cone-rod dystrophy and hearing loss 1

Benign:1

Jan 03, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.17

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.079

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

MetaRNN

Benign

0.0086

MetaSVM

Benign

-0.92

MutationAssessor

Uncertain

2.6

PhyloP100

7.4

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.0

REVEL

Benign

0.13

Sift

Benign

0.074

Sift4G

Benign

0.11

Polyphen

0.93

Vest4

0.59

MVP

0.82

MPC

0.11

ClinPred

0.016

GERP RS

6.0

Varity_R

0.13

gMVP

0.36

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.96

dbscSNV1_RF

Pathogenic

0.80

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over