9-78236421-C-T

Variant names:

• chr9-78236421-C-T
• rs1370536487
• NM_001330691.3:c.71C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001330691.3(CEP78):​c.71C>T​(p.Ala24Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,448,716 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A24T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CEP78 NM_001330691.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76
• 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: Uncertain_significance. The variant received 2 ACMG points.

• 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.71C>T	p.Ala24Val	missense	Exon 1 of 17	NP_001317620.1	Q5JTW2-3
	CEP78	NM_001098802.3		c.71C>T	p.Ala24Val	missense	Exon 1 of 16	NP_001092272.1	Q5JTW2-2
	CEP78	NM_001349838.2		c.71C>T	p.Ala24Val	missense	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.71C>T	p.Ala24Val	missense	Exon 1 of 17	ENSP00000496423.2	Q5JTW2-3
	CEP78	ENST00000376597.9	TSL:1	c.71C>T	p.Ala24Val	missense	Exon 1 of 16	ENSP00000365782.4	Q5JTW2-2
	CEP78	ENST00000643499.1		c.71C>T	p.Ala24Val	missense	Exon 1 of 17	ENSP00000495962.1	A0A2R8Y7A4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 221674 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: 6.90e-7 AC: 1 AN: 1448716 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719370

African (AFR) AF: 0.00 AC: 0 AN: 33258

American (AMR) AF: 0.00 AC: 0 AN: 43224

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25770

East Asian (EAS) AF: 0.00 AC: 0 AN: 39154

South Asian (SAS) AF: 0.00 AC: 0 AN: 84158

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51316

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1106228

Other (OTH) AF: 0.00 AC: 0 AN: 59860

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.21
Sift	Benign	0.082	T
Sift4G	Uncertain	0.049	D
Polyphen		1.0	D
Vest4		0.40
MutPred		0.54		Loss of sheet (P = 0.0817)
MVP		0.54
MPC		0.11
ClinPred		0.99	D
GERP RS		5.4
PromoterAI		0.098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.44
gMVP		0.57
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1370536487; hg19: chr9-80851337;