chr9-78236385-C-T

Variant names:

• chr9-78236385-C-T
• rs182452644
• NM_001330691.3:c.35C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001330691.3(CEP78):​c.35C>T​(p.Ala12Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,590,198 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 33)
  • Exomes 𝑓: 0.00043 (0 hom.)
• Consequence: CEP78 NM_001330691.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.84
• Publications: 6 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 (MetaRNN=0.0061234534).
• BP6: Variant 9-78236385-C-T is Benign according to our data. Variant chr9-78236385-C-T is described in ClinVar as Benign. ClinVar VariationId is 731106.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00336 (511/152274) while in subpopulation AFR AF = 0.0116 (481/41564). AF 95% confidence interval is 0.0107. There are 5 homozygotes in GnomAd4. There are 233 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

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.35C>T	p.Ala12Val	missense	Exon 1 of 17	NP_001317620.1	Q5JTW2-3
	CEP78	NM_001098802.3		c.35C>T	p.Ala12Val	missense	Exon 1 of 16	NP_001092272.1	Q5JTW2-2
	CEP78	NM_001349838.2		c.35C>T	p.Ala12Val	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.35C>T	p.Ala12Val	missense	Exon 1 of 17	ENSP00000496423.2	Q5JTW2-3
	CEP78	ENST00000376597.9	TSL:1	c.35C>T	p.Ala12Val	missense	Exon 1 of 16	ENSP00000365782.4	Q5JTW2-2
	CEP78	ENST00000643499.1		c.35C>T	p.Ala12Val	missense	Exon 1 of 17	ENSP00000495962.1	A0A2R8Y7A4

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 512 AN: 152156 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000891 AC: 182 AN: 204266 AF XY: 0.000721

Gnomad AFR exome AF: 0.0101

Gnomad AMR exome AF: 0.000642

Gnomad ASJ exome AF: 0.00415

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000786

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000427 AC: 614 AN: 1437924 Hom.: 0 Cov.: 30 AF XY: 0.000367 AC XY: 262 AN XY: 713570

African (AFR) AF: 0.0126 AC: 417 AN: 33030

American (AMR) AF: 0.000570 AC: 24 AN: 42088

Ashkenazi Jewish (ASJ) AF: 0.00327 AC: 84 AN: 25684

East Asian (EAS) AF: 0.00 AC: 0 AN: 38536

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47734

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5744

European-Non Finnish (NFE) AF: 0.0000209 AC: 23 AN: 1102296

Other (OTH) AF: 0.00104 AC: 62 AN: 59538

GnomAD4 genome AF: 0.00336 AC: 511 AN: 152274 Hom.: 5 Cov.: 33 AF XY: 0.00313 AC XY: 233 AN XY: 74440

African (AFR) AF: 0.0116 AC: 481 AN: 41564

American (AMR) AF: 0.000653 AC: 10 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5150

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68018

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00138 Hom.: 4

Bravo AF: 0.00349

ESP6500AA AF: 0.0108 AC: 41

ESP6500EA AF: 0.000370 AC: 3

ExAC AF: 0.000926 AC: 111

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	CEP78-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.53
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.068	T
Eigen	Benign	0.016
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0061	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.8
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.096
Sift	Uncertain	0.026	D
Sift4G	Uncertain	0.044	D
Polyphen		0.99	D
Vest4		0.10
MVP		0.59
MPC		0.11
ClinPred		0.042	T
GERP RS		3.1
PromoterAI		0.071	Neutral
Varity_R		0.13
gMVP		0.56
Mutation Taster		=99/1	polymorphism

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: rs182452644; hg19: chr9-80851301; COSMIC: COSV107315843;