9-78236385-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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, single submitter B:3
• Conservation: PhyloP100: 1.84

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 731106.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-78236385-C-T is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP78	NM_001330691.3	c.35C>T	p.Ala12Val	missense_variant	1/17	ENST00000643273.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP78	ENST00000643273.2	c.35C>T	p.Ala12Val	missense_variant	1/17		NM_001330691.3	P4

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

GnomAD3 exomes AF: 0.000891 AC: 182 AN: 204266 Hom.: 0 AF XY: 0.000721 AC XY: 81 AN XY: 112400

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 SAS 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

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.000570

Gnomad4 ASJ exome AF: 0.00327

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000120

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000209

Gnomad4 OTH exome AF: 0.00104

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

Gnomad4 AFR AF: 0.0116

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000612 Hom.: 2

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

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;.;.;.;.;.;.;.;.;T;.;.;.;.
Eigen	Benign	0.016
Eigen_PC	Benign	-0.044
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;.;T;T;T;T;T;T
MetaRNN	Benign	0.0061	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;M;M;M;.;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N;.;.;.;.;.;.;N;N;N;.;.;.;N
REVEL	Benign	0.096
Sift	Uncertain	0.026	D;.;.;.;.;.;.;D;D;D;.;.;.;D
Sift4G	Uncertain	0.044	D;.;.;.;.;.;.;D;D;D;.;.;.;D
Polyphen		0.99	D;.;.;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.10
MVP		0.59
MPC		0.11
ClinPred		0.042	T
GERP RS		3.1
Varity_R		0.13
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs182452644; hg19: chr9-80851301;