chr9-78236611-G-A

Variant names:

• chr9-78236611-G-A
• rs13292584
• NM_001330691.3:c.253+8G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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: Unknown, 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
• Usher syndrome type 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP78	NM_001330691.3	MANE Select	c.253+8G>A		splice_region intron	N/A	NP_001317620.1	Q5JTW2-3
	CEP78	NM_001098802.3		c.253+8G>A		splice_region intron	N/A	NP_001092272.1	Q5JTW2-2
	CEP78	NM_001349838.2		c.253+8G>A		splice_region intron	N/A	NP_001336767.1	A0A2R8YCP0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP78	ENST00000643273.2	MANE Select	c.253+8G>A		splice_region intron	N/A	ENSP00000496423.2	Q5JTW2-3
	CEP78	ENST00000376597.9	TSL:1	c.253+8G>A		splice_region intron	N/A	ENSP00000365782.4	Q5JTW2-2
	CEP78	ENST00000643499.1		c.253+8G>A		splice_region intron	N/A	ENSP00000495962.1	A0A2R8Y7A4

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

GnomAD2 exomes AF: 0.350 AC: 60191 AN: 171744 AF XY: 0.359

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 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

African (AFR) AF: 0.157 AC: 4715 AN: 30068

American (AMR) AF: 0.321 AC: 9639 AN: 30018

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 7838 AN: 20194

East Asian (EAS) AF: 0.249 AC: 9546 AN: 38382

South Asian (SAS) AF: 0.385 AC: 27462 AN: 71418

European-Finnish (FIN) AF: 0.375 AC: 18750 AN: 49994

Middle Eastern (MID) AF: 0.395 AC: 2109 AN: 5340

European-Non Finnish (NFE) AF: 0.383 AC: 409008 AN: 1069154

Other (OTH) AF: 0.365 AC: 20583 AN: 56348

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

African (AFR) AF: 0.171 AC: 7097 AN: 41524

American (AMR) AF: 0.332 AC: 5077 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1328 AN: 3472

East Asian (EAS) AF: 0.277 AC: 1427 AN: 5144

South Asian (SAS) AF: 0.370 AC: 1782 AN: 4820

European-Finnish (FIN) AF: 0.369 AC: 3908 AN: 10578

Middle Eastern (MID) AF: 0.432 AC: 126 AN: 292

European-Non Finnish (NFE) AF: 0.392 AC: 26628 AN: 67952

Other (OTH) AF: 0.340 AC: 718 AN: 2114

Alfa AF: 0.340 Hom.: 2705

Bravo AF: 0.308

Asia WGS AF: 0.291 AC: 1014 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	13
DANN	Benign	0.79
PhyloP100		1.4
PromoterAI		-0.071	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13292584; hg19: chr9-80851527; COSMIC: COSV52847140;