9-78236227-C-T

Variant names:

• chr9-78236227-C-T
• rs115171840
• NM_001330691.3:c.-124C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001330691.3(CEP78):​c.-124C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0453 in 824,166 control chromosomes in the GnomAD database, including 1,311 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.063 (410 hom., cov: 33)
  • Exomes 𝑓: 0.041 (901 hom.)
• Consequence: CEP78 NM_001330691.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.10
• Publications: 2 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: AR, Unknown Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen
• cone-rod dystrophy and hearing loss 1

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Usher syndrome type 3

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000289440 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 9-78236227-C-T is Benign according to our data. Variant chr9-78236227-C-T is described in ClinVar as Benign. ClinVar VariationId is 1264250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

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.-124C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	NP_001317620.1	Q5JTW2-3
	CEP78	NM_001330691.3	MANE Select	c.-124C>T		5_prime_UTR	Exon 1 of 17	NP_001317620.1	Q5JTW2-3
	CEP78	NM_001098802.3		c.-124C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_001092272.1	Q5JTW2-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP78	ENST00000643273.2	MANE Select	c.-124C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 17	ENSP00000496423.2	Q5JTW2-3
	CEP78	ENST00000376597.9	TSL:1	c.-124C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000365782.4	Q5JTW2-2
	CEP78	ENST00000643273.2	MANE Select	c.-124C>T		5_prime_UTR	Exon 1 of 17	ENSP00000496423.2	Q5JTW2-3

Frequencies

GnomAD3 genomes AF: 0.0631 AC: 9598 AN: 152088 Hom.: 405 Cov.: 33

Gnomad AFR AF: 0.0887

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.106

Gnomad ASJ AF: 0.0381

Gnomad EAS AF: 0.103

Gnomad SAS AF: 0.0669

Gnomad FIN AF: 0.111

Gnomad MID AF: 0.0223

Gnomad NFE AF: 0.0295

Gnomad OTH AF: 0.0584

GnomAD4 exome AF: 0.0413 AC: 27748 AN: 671962 Hom.: 901 Cov.: 9 AF XY: 0.0413 AC XY: 14302 AN XY: 346556

African (AFR) AF: 0.0933 AC: 1285 AN: 13770

American (AMR) AF: 0.146 AC: 2799 AN: 19128

Ashkenazi Jewish (ASJ) AF: 0.0376 AC: 546 AN: 14538

East Asian (EAS) AF: 0.0799 AC: 2358 AN: 29514

South Asian (SAS) AF: 0.0587 AC: 2958 AN: 50374

European-Finnish (FIN) AF: 0.0929 AC: 2766 AN: 29778

Middle Eastern (MID) AF: 0.0373 AC: 90 AN: 2412

European-Non Finnish (NFE) AF: 0.0280 AC: 13400 AN: 479208

Other (OTH) AF: 0.0465 AC: 1546 AN: 33240

GnomAD4 genome AF: 0.0632 AC: 9617 AN: 152204 Hom.: 410 Cov.: 33 AF XY: 0.0676 AC XY: 5034 AN XY: 74414

African (AFR) AF: 0.0885 AC: 3676 AN: 41548

American (AMR) AF: 0.107 AC: 1637 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0381 AC: 132 AN: 3468

East Asian (EAS) AF: 0.102 AC: 524 AN: 5136

South Asian (SAS) AF: 0.0674 AC: 325 AN: 4824

European-Finnish (FIN) AF: 0.111 AC: 1181 AN: 10614

Middle Eastern (MID) AF: 0.0240 AC: 7 AN: 292

European-Non Finnish (NFE) AF: 0.0295 AC: 2003 AN: 67992

Other (OTH) AF: 0.0611 AC: 129 AN: 2110

Alfa AF: 0.0255 Hom.: 26

Bravo AF: 0.0671

Asia WGS AF: 0.0870 AC: 303 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.2
DANN	Benign	0.76
PhyloP100		-1.1
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=300/0	polymorphism (auto)

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: rs115171840; hg19: chr9-80851143;