9-78248353-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

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 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 criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.39

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

Verdict is Benign. Variant got -15 ACMG points.

• PP3: Splicing scoreres supports a deletorius 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]. Clinvar id is 517540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-78248353-G-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 15 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP78	NM_001330691.3	c.955G>C	p.Glu319Gln	missense_variant, splice_region_variant	7/17	ENST00000643273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP78	ENST00000643273.2	c.955G>C	p.Glu319Gln	missense_variant, splice_region_variant	7/17		NM_001330691.3	P4

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1338 AN: 152114 Hom.: 15 Cov.: 32

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

GnomAD3 exomes AF: 0.00216 AC: 537 AN: 248466 Hom.: 7 AF XY: 0.00164 AC XY: 221 AN XY: 134822

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 SAS exome AF: 0.000131

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.: 15 Cov.: 24 AF XY: 0.000809 AC XY: 568 AN XY: 702118

Gnomad4 AFR exome AF: 0.0295

Gnomad4 AMR exome AF: 0.00226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000824

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.00255

GnomAD4 genome AF: 0.00887 AC: 1351 AN: 152232 Hom.: 16 Cov.: 32 AF XY: 0.00825 AC XY: 614 AN XY: 74438

Gnomad4 AFR AF: 0.0303

Gnomad4 AMR AF: 0.00412

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.000454 Hom.: 1

Bravo AF: 0.00992

ESP6500AA AF: 0.0284 AC: 103

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00237 AC: 286

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000328

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

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). -

Cone-rod dystrophy and hearing loss 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 03, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Benign	0.079	T;.;.;.;.;.;.;.;.;T;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;.;T;T;T;T;T;T
MetaRNN	Benign	0.0086	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	M;.;.;.;.;.;M;M;M;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N;.;.;.;.;.;.;N;N;N;.;.;.;N
REVEL	Benign	0.13
Sift	Benign	0.074	T;.;.;.;.;.;.;T;T;T;.;.;.;T
Sift4G	Benign	0.11	T;.;.;.;.;.;.;T;T;T;.;.;.;T
Polyphen		0.93	P;.;.;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.59
MVP		0.82
MPC		0.11
ClinPred		0.016	T
GERP RS		6.0
Varity_R		0.13
gMVP		0.36

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

LitVar

Other links and lift over

dbSNP: rs61730338; hg19: chr9-80863269;