rs61730338

Variant names:

• chr9-78248353-G-C
• rs61730338
• NM_001330691.3:c.955G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-78248353-G-C
• chr9-78248353-G-A

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 1P and 16B. PP3 BP6_Very_Strong BS1 BS2

The NM_001330691.3(CEP78):​c.955G>C​(p.Glu319Gln) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,555,972 control chromosomes in the GnomAD database, including 31 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E319E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0089 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00093 (15 hom.)
• Consequence: CEP78 NM_001330691.3 missense, splice_region
• Scores: Splicing: ADA: 0.9579
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 7.39
• Publications: 7 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 -15 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BP6: Variant 9-78248353-G-C is Benign according to our data. Variant chr9-78248353-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 517540.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 = 0.00887 (1351/152232) while in subpopulation AFR AF = 0.0303 (1260/41542). AF 95% confidence interval is 0.0289. There are 16 homozygotes in GnomAd4. There are 614 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 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.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 17	NP_001317620.1	Q5JTW2-3
	CEP78	NM_001098802.3		c.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 16	NP_001092272.1	Q5JTW2-2
	CEP78	NM_001349838.2		c.955G>C	p.Glu319Gln	missense splice_region	Exon 7 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.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 17	ENSP00000496423.2	Q5JTW2-3
	CEP78	ENST00000376597.9	TSL:1	c.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 16	ENSP00000365782.4	Q5JTW2-2
	CEP78	ENST00000643499.1		c.955G>C	p.Glu319Gln	missense splice_region	Exon 7 of 17	ENSP00000495962.1	A0A2R8Y7A4

Frequencies

GnomAD3 genomes AF: 0.00880 AC: 1338 AN: 152114 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00412

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00909

GnomAD2 exomes AF: 0.00216 AC: 537 AN: 248466 AF XY: 0.00164

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.000932 AC: 1308 AN: 1403740 Hom.: 15 Cov.: 24 AF XY: 0.000809 AC XY: 568 AN XY: 702118

African (AFR) AF: 0.0295 AC: 952 AN: 32220

American (AMR) AF: 0.00226 AC: 101 AN: 44612

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25732

East Asian (EAS) AF: 0.00 AC: 0 AN: 39426

South Asian (SAS) AF: 0.0000824 AC: 7 AN: 84974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00354 AC: 20 AN: 5656

European-Non Finnish (NFE) AF: 0.0000746 AC: 79 AN: 1059410

Other (OTH) AF: 0.00255 AC: 149 AN: 58362

GnomAD4 genome AF: 0.00887 AC: 1351 AN: 152232 Hom.: 16 Cov.: 32 AF XY: 0.00825 AC XY: 614 AN XY: 74438

African (AFR) AF: 0.0303 AC: 1260 AN: 41542

American (AMR) AF: 0.00412 AC: 63 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68006

Other (OTH) AF: 0.00900 AC: 19 AN: 2112

Alfa AF: 0.000454 Hom.: 1

Bravo AF: 0.00992

ESP6500AA AF: 0.0284 AC: 103

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00237 AC: 286

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000328

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Cone-rod dystrophy and hearing loss 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.079	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		7.4
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.13
Sift	Benign	0.074	T
Sift4G	Benign	0.11	T
Polyphen		0.93	P
Vest4		0.59
MVP		0.82
MPC		0.11
ClinPred		0.016	T
GERP RS		6.0
Varity_R		0.13
gMVP		0.36
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Pathogenic	0.80
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: rs61730338; hg19: chr9-80863269;