rs148455387

chr1-3836504-T-Achr1-3836504-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_014704.4(CEP104):c.1308A>T(p.Gly436=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00548 in 1,386,786 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0031 (2 hom., cov: 23)
  • Exomes 𝑓: 0.0057 (17 hom.)
• Consequence: CEP104 NM_014704.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00400

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 1-3836504-T-A is Benign according to our data. Variant chr1-3836504-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 475456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.004 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00314 (408/130098) while in subpopulation NFE AF= 0.0049 (306/62424). AF 95% confidence interval is 0.00445. There are 2 homozygotes in gnomad4. There are 189 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP104	NM_014704.4	c.1308A>T	p.Gly436=	synonymous_variant	10/22	ENST00000378230.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP104	ENST00000378230.8	c.1308A>T	p.Gly436=	synonymous_variant	10/22	5	NM_014704.4	P4

Frequencies

GnomAD3 genomes AF: 0.00314 AC: 408 AN: 129970 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.000850

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00383

Gnomad ASJ AF: 0.00123

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00294

Gnomad FIN AF: 0.000995

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00490

Gnomad OTH AF: 0.00353

GnomAD3 exomes AF: 0.00273 AC: 670 AN: 245616 Hom.: 1 AF XY: 0.00275 AC XY: 365 AN XY: 132962

Gnomad AFR exome AF: 0.000808

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.00151

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00197

Gnomad FIN exome AF: 0.000558

Gnomad NFE exome AF: 0.00419

Gnomad OTH exome AF: 0.00248

GnomAD4 exome AF: 0.00572 AC: 7194 AN: 1256688 Hom.: 17 Cov.: 31 AF XY: 0.00559 AC XY: 3526 AN XY: 631190

Gnomad4 AFR exome AF: 0.00129

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00152

Gnomad4 EAS exome AF: 0.0000289

Gnomad4 SAS exome AF: 0.00213

Gnomad4 FIN exome AF: 0.000856

Gnomad4 NFE exome AF: 0.00684

Gnomad4 OTH exome AF: 0.00546

GnomAD4 genome AF: 0.00314 AC: 408 AN: 130098 Hom.: 2 Cov.: 23 AF XY: 0.00306 AC XY: 189 AN XY: 61830

Gnomad4 AFR AF: 0.000848

Gnomad4 AMR AF: 0.00382

Gnomad4 ASJ AF: 0.00123

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00293

Gnomad4 FIN AF: 0.000995

Gnomad4 NFE AF: 0.00490

Gnomad4 OTH AF: 0.00348

Alfa AF: 0.00355 Hom.: 1

EpiCase AF: 0.00475

EpiControl AF: 0.00369

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 25 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

CEP104: BP4, BP7, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
Cadd	Benign	1.0
Dann	Benign	0.67
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs148455387; hg19: chr1-3753068; COSMIC: COSV65517764; COSMIC: COSV65517764;