rs1057518753

Variant names:

• chr9-78265370-A-G
• rs1057518753
• NM_001330691.3:c.1626-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001330691.3(CEP78):​c.1626-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,423,110 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CEP78 NM_001330691.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.38
• Publications: 4 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.4, offset of -38, new splice context is: ctgttcttatgtgcttctAGtaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-78265370-A-G is Pathogenic according to our data. Variant chr9-78265370-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 372272.Status of the report is no_assertion_criteria_provided, 0 stars.

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.1626-2A>G		splice_acceptor intron	N/A	NP_001317620.1	Q5JTW2-3
	CEP78	NM_001098802.3		c.1629-2A>G		splice_acceptor intron	N/A	NP_001092272.1	Q5JTW2-2
	CEP78	NM_001349838.2		c.1626-2A>G		splice_acceptor 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.1626-2A>G		splice_acceptor intron	N/A	ENSP00000496423.2	Q5JTW2-3
	CEP78	ENST00000376597.9	TSL:1	c.1629-2A>G		splice_acceptor intron	N/A	ENSP00000365782.4	Q5JTW2-2
	CEP78	ENST00000447629.2	TSL:1	n.268-2A>G		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1423110 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 705518

African (AFR) AF: 0.00 AC: 0 AN: 31516

American (AMR) AF: 0.00 AC: 0 AN: 35948

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24284

East Asian (EAS) AF: 0.00 AC: 0 AN: 39220

South Asian (SAS) AF: 0.00 AC: 0 AN: 78062

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52514

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5580

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097298

Other (OTH) AF: 0.00 AC: 0 AN: 58688

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Cone-rod dystrophy and hearing loss 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.96
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.4
GERP RS		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.92		Position offset: 12
DS_AL_spliceai		1.0		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057518753; hg19: chr9-80880286;