rs2275829

chr1-3829920-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014704.4(CEP104):c.1914A>G(p.Arg638=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00454 in 1,614,168 control chromosomes in the GnomAD database, including 401 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (38 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (363 hom.)
• Consequence: CEP104 NM_014704.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.56

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=-0.82).
• BP6: Variant 1-3829920-T-C is Benign according to our data. Variant chr1-3829920-T-C is described in ClinVar as [Benign]. Clinvar id is 475460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.56 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP104	NM_014704.4	c.1914A>G	p.Arg638=	synonymous_variant	14/22	ENST00000378230.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP104	ENST00000378230.8	c.1914A>G	p.Arg638=	synonymous_variant	14/22	5	NM_014704.4	P4

Frequencies

GnomAD3 genomes AF: 0.00531 AC: 808 AN: 152176 Hom.: 38 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.108

Gnomad SAS AF: 0.00394

Gnomad FIN AF: 0.0159

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00240

GnomAD3 exomes AF: 0.00897 AC: 2255 AN: 251494 Hom.: 96 AF XY: 0.00834 AC XY: 1133 AN XY: 135922

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0961

Gnomad SAS exome AF: 0.00176

Gnomad FIN exome AF: 0.0143

Gnomad NFE exome AF: 0.000774

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00446 AC: 6513 AN: 1461874 Hom.: 363 Cov.: 33 AF XY: 0.00431 AC XY: 3135 AN XY: 727240

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.000880

Gnomad4 EAS exome AF: 0.125

Gnomad4 SAS exome AF: 0.00182

Gnomad4 FIN exome AF: 0.0152

Gnomad4 NFE exome AF: 0.000302

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00531 AC: 809 AN: 152294 Hom.: 38 Cov.: 33 AF XY: 0.00664 AC XY: 494 AN XY: 74452

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.108

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0159

Gnomad4 NFE AF: 0.000617

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000990 Hom.: 1

Bravo AF: 0.00464

Asia WGS AF: 0.0290 AC: 101 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: 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 12, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	3.3
Dann	Benign	0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2275829; hg19: chr1-3746484; COSMIC: COSV65517537; COSMIC: COSV65517537;