9-78243456-T-G

Variant names:

• chr9-78243456-T-G
• rs17064247
• NM_001330691.3:c.604-6T>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001098802.3(CEP78):​c.604-6T>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00324 in 1,608,776 control chromosomes in the GnomAD database, including 132 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 0.017 (64 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (68 hom.)
• Consequence: CEP78 NM_001098802.3 splice_region, intron
• Scores: Splicing: ADA: 0.5007
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.50
• Publications: 3 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: 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, PanelApp Australia
• Usher syndrome type 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 9-78243456-T-G is Benign according to our data. Variant chr9-78243456-T-G is described in ClinVar as Benign. ClinVar VariationId is 517537.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0572 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001098802.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP78	NM_001330691.3	MANE Select	c.604-6T>G		splice_region intron	N/A	NP_001317620.1
	CEP78	NM_001098802.3		c.604-6T>G		splice_region intron	N/A	NP_001092272.1
	CEP78	NM_001349838.2		c.604-6T>G		splice_region intron	N/A	NP_001336767.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP78	ENST00000643273.2	MANE Select	c.604-6T>G		splice_region intron	N/A	ENSP00000496423.2
	CEP78	ENST00000376597.9	TSL:1	c.604-6T>G		splice_region intron	N/A	ENSP00000365782.4
	CEP78	ENST00000643499.1		c.604-6T>G		splice_region intron	N/A	ENSP00000495962.1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2621 AN: 152188 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.0592

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00478 AC: 1167 AN: 244158 AF XY: 0.00358

Gnomad AFR exome AF: 0.0658

Gnomad AMR exome AF: 0.00315

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000270

Gnomad OTH exome AF: 0.00220

GnomAD4 exome AF: 0.00178 AC: 2586 AN: 1456470 Hom.: 68 Cov.: 29 AF XY: 0.00157 AC XY: 1136 AN XY: 724526

African (AFR) AF: 0.0598 AC: 1983 AN: 33138

American (AMR) AF: 0.00417 AC: 182 AN: 43658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25818

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.000258 AC: 22 AN: 85234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53340

Middle Eastern (MID) AF: 0.00488 AC: 28 AN: 5740

European-Non Finnish (NFE) AF: 0.000106 AC: 118 AN: 1109804

Other (OTH) AF: 0.00421 AC: 253 AN: 60126

GnomAD4 genome AF: 0.0173 AC: 2628 AN: 152306 Hom.: 64 Cov.: 32 AF XY: 0.0165 AC XY: 1228 AN XY: 74476

African (AFR) AF: 0.0592 AC: 2459 AN: 41546

American (AMR) AF: 0.00882 AC: 135 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.0109 AC: 23 AN: 2112

Alfa AF: 0.00894 Hom.: 22

Bravo AF: 0.0200

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.000383

EpiControl AF: 0.000297

ClinVar

ClinVar submissions as Germline

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	-0.37
CADD	Benign	13
DANN	Benign	0.91
PhyloP100		1.5
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.50
dbscSNV1_RF	Benign	0.70
SpliceAI score (max)		0.030		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: rs17064247; hg19: chr9-80858372;