chr9-78266441-G-C

Variant names:

• chr9-78266441-G-C
• rs146563928
• NM_001330691.3:c.1846-1G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_Strong BS1 BS2

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: Splicing: ADA: 1.000
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 1.12

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]

ACMG classification

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
CEP78	NM_001330691.3	c.1846-1G>C		splice_acceptor_variant, intron_variant	Intron 15 of 16	ENST00000643273.2	NP_001317620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP78	ENST00000643273.2	c.1846-1G>C		splice_acceptor_variant, intron_variant	Intron 15 of 16		NM_001330691.3	ENSP00000496423.2

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 152040 Hom.: 1 Cov.: 32

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

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

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

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152158 Hom.: 1 Cov.: 32 AF XY: 0.00161 AC XY: 120 AN XY: 74370

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

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:3 Benign:3

Revision: criteria provided, conflicting classifications

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
PhyloP100		1.1
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

Other links and lift over

dbSNP: rs146563928; hg19: chr9-80881357;