1-3826786-G-C

Variant names:

• chr1-3826786-G-C
• rs58111155
• NM_014704.4:c.2152-42C>G

Variant summary

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

The NM_014704.4(CEP104):​c.2152-42C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0283 in 1,559,322 control chromosomes in the GnomAD database, including 1,210 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (107 hom., cov: 34)
  • Exomes 𝑓: 0.029 (1103 hom.)
• Consequence: CEP104 NM_014704.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.120
• Publications: 4 publications found

Genes affected

CEP104 (HGNC:24866): (centrosomal protein 104) This gene encodes a centrosomal protein required for ciliogenesis and for ciliary tip structural integrity. The mammalian protein contains three amino-terminal hydrophobic domains, two glycosylation sites, four cysteine-rich motifs, and two regions with homology to the glutamate receptor ionotropic, NMDA 1 protein. During ciliogenesis, the encoded protein translocates from the distal tips of the centrioles to the tip of the elongating cilium. Knockdown of the protein in human retinal pigment cells results in severe defects in ciliogenesis with structural deformities at the ciliary tips. Allelic variants of this gene are associated with the autosomal-recessive disorder Joubert syndrome, which is characterized by a distinctive mid-hindbrain and cerebellar malformation, oculomotor apraxia, irregular breathing, developmental delay, and ataxia. [provided by RefSeq, Feb 2016]

CEP104 Gene-Disease associations (from GenCC):

• Joubert syndrome 25

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Joubert syndrome

  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 (BayesDel_noAF=-0.91).
• BP6: Variant 1-3826786-G-C is Benign according to our data. Variant chr1-3826786-G-C is described in ClinVar as Benign. ClinVar VariationId is 1288966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0974 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014704.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP104	NM_014704.4	MANE Select	c.2152-42C>G		intron	N/A	NP_055519.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP104	ENST00000378230.8	TSL:5 MANE Select	c.2152-42C>G		intron	N/A	ENSP00000367476.3
	CEP104	ENST00000675666.1		c.2152-42C>G		intron	N/A	ENSP00000502548.1
	CEP104	ENST00000676052.1		c.2170-42C>G		intron	N/A	ENSP00000502793.1

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3852 AN: 152194 Hom.: 108 Cov.: 34

Gnomad AFR AF: 0.0136

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0426

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0841

Gnomad FIN AF: 0.0228

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0459 AC: 11471 AN: 250152 AF XY: 0.0461

Gnomad AFR exome AF: 0.0131

Gnomad AMR exome AF: 0.0887

Gnomad ASJ exome AF: 0.0543

Gnomad EAS exome AF: 0.120

Gnomad FIN exome AF: 0.0235

Gnomad NFE exome AF: 0.0188

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0286 AC: 40278 AN: 1407010 Hom.: 1103 Cov.: 27 AF XY: 0.0300 AC XY: 21082 AN XY: 703564

African (AFR) AF: 0.0131 AC: 418 AN: 31800

American (AMR) AF: 0.0820 AC: 3634 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.0525 AC: 1349 AN: 25718

East Asian (EAS) AF: 0.120 AC: 4711 AN: 39358

South Asian (SAS) AF: 0.0846 AC: 7175 AN: 84790

European-Finnish (FIN) AF: 0.0265 AC: 1415 AN: 53392

Middle Eastern (MID) AF: 0.0598 AC: 337 AN: 5636

European-Non Finnish (NFE) AF: 0.0181 AC: 19281 AN: 1063598

Other (OTH) AF: 0.0335 AC: 1958 AN: 58392

GnomAD4 genome AF: 0.0253 AC: 3851 AN: 152312 Hom.: 107 Cov.: 34 AF XY: 0.0269 AC XY: 2001 AN XY: 74488

African (AFR) AF: 0.0136 AC: 567 AN: 41560

American (AMR) AF: 0.0425 AC: 650 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0521 AC: 181 AN: 3472

East Asian (EAS) AF: 0.105 AC: 543 AN: 5186

South Asian (SAS) AF: 0.0839 AC: 405 AN: 4826

European-Finnish (FIN) AF: 0.0228 AC: 242 AN: 10622

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0173 AC: 1175 AN: 68024

Other (OTH) AF: 0.0312 AC: 66 AN: 2116

Alfa AF: 0.0271 Hom.: 13

Bravo AF: 0.0268

Asia WGS AF: 0.0790 AC: 273 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 21, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.7
DANN	Benign	0.43
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs58111155; hg19: chr1-3743350; COSMIC: COSV65516633; COSMIC: COSV65516633;