9-78236351-A-G

Variant names:

• chr9-78236351-A-G
• rs761538280
• NM_001330691.3:c.1A>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001330691.3(CEP78):​c.1A>G​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000211 in 1,418,920 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CEP78 NM_001330691.3 start_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.36
• Publications: 0 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: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 6 pathogenic variants. Next in-frame start position is after 88 codons. Genomic position: 78240031. Lost 0.124 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.1A>G	p.Met1?	start_lost	Exon 1 of 17	NP_001317620.1	Q5JTW2-3
	CEP78	NM_001098802.3		c.1A>G	p.Met1?	start_lost	Exon 1 of 16	NP_001092272.1	Q5JTW2-2
	CEP78	NM_001349838.2		c.1A>G	p.Met1?	start_lost	Exon 1 of 16	NP_001336767.1	A0A2R8YCP0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP78	ENST00000643273.2	MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 17	ENSP00000496423.2	Q5JTW2-3
	CEP78	ENST00000376597.9	TSL:1	c.1A>G	p.Met1?	start_lost	Exon 1 of 16	ENSP00000365782.4	Q5JTW2-2
	CEP78	ENST00000643499.1		c.1A>G	p.Met1?	start_lost	Exon 1 of 17	ENSP00000495962.1	A0A2R8Y7A4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000559 AC: 1 AN: 178920 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1418920 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 703194

African (AFR) AF: 0.00 AC: 0 AN: 32574

American (AMR) AF: 0.00 AC: 0 AN: 39904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 37480

South Asian (SAS) AF: 0.0000122 AC: 1 AN: 81942

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 41736

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5616

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1095166

Other (OTH) AF: 0.00 AC: 0 AN: 58990

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000846 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.56	T
PhyloP100		5.4
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.53
MutPred		0.99		Loss of ubiquitination at K6 (P = 0.0935)
MVP		0.73
ClinPred		1.0	D
GERP RS		4.7
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.95
gMVP		0.62
Mutation Taster		=15/185	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs761538280; hg19: chr9-80851267;