chr9-78266441-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_StrongBS1BS2

The NM_001330691.3(CEP78):​c.1846-1G>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0031 in 1,578,644 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)
Exomes 𝑓: 0.0032 ( 11 hom. )

Consequence

CEP78
NM_001330691.3 splice_acceptor, intron

Scores

3
3
1
Splicing: ADA: 1.000
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3

Conservation

PhyloP100: 1.12
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.1237016 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 6, new splice context is: gtttttccttctactttcAGaaa. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
BS1
Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00185 (282/152158) while in subpopulation NFE AF = 0.00335 (228/68002). AF 95% confidence interval is 0.003. There are 1 homozygotes in GnomAd4. There are 120 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
BS2
High Homozygotes in GnomAdExome4 at 11 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CEP78NM_001330691.3 linkc.1846-1G>C splice_acceptor_variant, intron_variant Intron 15 of 16 ENST00000643273.2 NP_001317620.1 Q5JTW2-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CEP78ENST00000643273.2 linkc.1846-1G>C splice_acceptor_variant, intron_variant Intron 15 of 16 NM_001330691.3 ENSP00000496423.2 Q5JTW2-3

Frequencies

GnomAD3 genomes
AF:
0.00185
AC:
281
AN:
152040
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000580
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000459
Gnomad ASJ
AF:
0.00231
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00104
Gnomad FIN
AF:
0.000189
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00335
Gnomad OTH
AF:
0.00335
GnomAD2 exomes
AF:
0.00187
AC:
425
AN:
226736
AF XY:
0.00205
show subpopulations
Gnomad AFR exome
AF:
0.000667
Gnomad AMR exome
AF:
0.000316
Gnomad ASJ exome
AF:
0.00298
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000146
Gnomad NFE exome
AF:
0.00288
Gnomad OTH exome
AF:
0.00167
GnomAD4 exome
AF:
0.00324
AC:
4619
AN:
1426486
Hom.:
11
Cov.:
29
AF XY:
0.00327
AC XY:
2311
AN XY:
705958
show subpopulations
African (AFR)
AF:
0.000378
AC:
12
AN:
31758
American (AMR)
AF:
0.000235
AC:
9
AN:
38308
Ashkenazi Jewish (ASJ)
AF:
0.00268
AC:
66
AN:
24624
East Asian (EAS)
AF:
0.0000255
AC:
1
AN:
39162
South Asian (SAS)
AF:
0.00241
AC:
195
AN:
81014
European-Finnish (FIN)
AF:
0.000344
AC:
18
AN:
52394
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5590
European-Non Finnish (NFE)
AF:
0.00377
AC:
4130
AN:
1094812
Other (OTH)
AF:
0.00320
AC:
188
AN:
58824
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.479
Heterozygous variant carriers
0
205
410
616
821
1026
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
166
332
498
664
830
<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:
0.00185
AC:
282
AN:
152158
Hom.:
1
Cov.:
32
AF XY:
0.00161
AC XY:
120
AN XY:
74370
show subpopulations
African (AFR)
AF:
0.000578
AC:
24
AN:
41504
American (AMR)
AF:
0.000458
AC:
7
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00231
AC:
8
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5182
South Asian (SAS)
AF:
0.00125
AC:
6
AN:
4818
European-Finnish (FIN)
AF:
0.000189
AC:
2
AN:
10578
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00335
AC:
228
AN:
68002
Other (OTH)
AF:
0.00331
AC:
7
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
14
29
43
58
72
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<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:
0.00319
Hom.:
2
Bravo
AF:
0.00179
TwinsUK
AF:
0.00297
AC:
11
ALSPAC
AF:
0.00441
AC:
17
ESP6500AA
AF:
0.000272
AC:
1
ESP6500EA
AF:
0.00257
AC:
21
ExAC
AF:
0.00172
AC:
208
EpiCase
AF:
0.00301
EpiControl
AF:
0.00291

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:2
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jun 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

CEP78: PVS1:Moderate, BS2 -

not specified Uncertain:1
Jul 24, 2019
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The c.1849-1G>C variant in CEP78 has not been previously reported in individuals with rod-cone dystrophy, but has been reported by our laboratory in the heterozygous state in 5 individuals with hearing loss, including 2 who had alternate explanations of the hearing loss. This variant has been identified in 0.3% (350/120170) of European chromosomes, including 2 homozygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs146563928). This variant occurs in the last exon of the gene and it is in the invariant region (+/- 1,2) of the splice consensus sequence and is expected to impact the splice site. Computation splice tools suggests the variant creates a cryptic 3' splice site 6 bp downstream of the original splice site which is predicted to result in an in-frame deletion of two amino acids; however these tools may not accurately reflect impact of the variant on splicing. While the clinical significance of the c.1849-1G>C variant is uncertain, the frequency data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, BP5, PP3. -

Cone-rod dystrophy and hearing loss 1 Uncertain:1
Nov 13, 2023
Revvity Omics, Revvity
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Retinal dystrophy Uncertain:1
Jan 01, 2022
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

CEP78-related disorder Benign:1
Feb 24, 2023
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Uncertain
0.080
CADD
Pathogenic
35
DANN
Uncertain
0.98
Eigen
Pathogenic
1.0
Eigen_PC
Pathogenic
0.85
FATHMM_MKL
Uncertain
0.76
D
GERP RS
4.0
Mutation Taster
=93/7
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.94
SpliceAI score (max)
1.0
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.82
Position offset: 7
DS_AL_spliceai
1.0
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs146563928; hg19: chr9-80881357; API