rs13292584

Positions:

• chr9-78236611-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001330691.3(CEP78):​c.253+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.366 in 1,523,010 control chromosomes in the GnomAD database, including 104,533 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8440 hom., cov: 32)
  • Exomes 𝑓: 0.37 (96093 hom.)
• Consequence: CEP78 NM_001330691.3 splice_region, intron
• Scores: Splicing: ADA: 0.004088
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.36

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-78236611-G-A is Benign according to our data. Variant chr9-78236611-G-A is described in ClinVar as [Benign]. Clinvar id is 517539.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP78	NM_001330691.3	c.253+8G>A		splice_region_variant, intron_variant		ENST00000643273.2	NP_001317620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP78	ENST00000643273.2	c.253+8G>A		splice_region_variant, intron_variant			NM_001330691.3	ENSP00000496423	P4

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48371 AN: 151976 Hom.: 8440 Cov.: 32

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.332

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.341

GnomAD3 exomes AF: 0.350 AC: 60191 AN: 171744 Hom.: 10796 AF XY: 0.359 AC XY: 32910 AN XY: 91576

Gnomad AFR exome AF: 0.163

Gnomad AMR exome AF: 0.324

Gnomad ASJ exome AF: 0.396

Gnomad EAS exome AF: 0.267

Gnomad SAS exome AF: 0.385

Gnomad FIN exome AF: 0.369

Gnomad NFE exome AF: 0.391

Gnomad OTH exome AF: 0.372

GnomAD4 exome AF: 0.372 AC: 509650 AN: 1370916 Hom.: 96093 Cov.: 36 AF XY: 0.373 AC XY: 251092 AN XY: 672656

Gnomad4 AFR exome AF: 0.157

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.388

Gnomad4 EAS exome AF: 0.249

Gnomad4 SAS exome AF: 0.385

Gnomad4 FIN exome AF: 0.375

Gnomad4 NFE exome AF: 0.383

Gnomad4 OTH exome AF: 0.365

GnomAD4 genome AF: 0.318 AC: 48392 AN: 152094 Hom.: 8440 Cov.: 32 AF XY: 0.318 AC XY: 23666 AN XY: 74342

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.332

Gnomad4 ASJ AF: 0.382

Gnomad4 EAS AF: 0.277

Gnomad4 SAS AF: 0.370

Gnomad4 FIN AF: 0.369

Gnomad4 NFE AF: 0.392

Gnomad4 OTH AF: 0.340

Alfa AF: 0.343 Hom.: 2693

Bravo AF: 0.308

Asia WGS AF: 0.291 AC: 1014 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

c.253+8G>A in intron 1 of CEP78: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 41.93% (3473/8282) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs13292584). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0041
dbscSNV1_RF	Benign	0.0080
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: rs13292584; hg19: chr9-80851527; COSMIC: COSV52847140;