rs6663840

chr1-3826755-G-Achr1-3826755-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014704.4(CEP104):c.2152-11C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,611,218 control chromosomes in the GnomAD database, including 95,404 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12838 hom., cov: 33)
  • Exomes 𝑓: 0.33 (82566 hom.)
• Consequence: CEP104 NM_014704.4 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001617
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.184

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 1-3826755-G-A is Benign according to our data. Variant chr1-3826755-G-A is described in ClinVar as [Benign]. Clinvar id is 1209725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.55 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP104	NM_014704.4	c.2152-11C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000378230.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP104	ENST00000378230.8	c.2152-11C>T		splice_polypyrimidine_tract_variant, intron_variant		5	NM_014704.4	P4

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59498 AN: 151900 Hom.: 12816 Cov.: 33

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.252

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.365

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.508

Gnomad FIN AF: 0.322

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.369

GnomAD3 exomes AF: 0.381 AC: 95695 AN: 251236 Hom.: 19552 AF XY: 0.380 AC XY: 51623 AN XY: 135798

Gnomad AFR exome AF: 0.557

Gnomad AMR exome AF: 0.393

Gnomad ASJ exome AF: 0.383

Gnomad EAS exome AF: 0.557

Gnomad SAS exome AF: 0.510

Gnomad FIN exome AF: 0.315

Gnomad NFE exome AF: 0.303

Gnomad OTH exome AF: 0.350

GnomAD4 exome AF: 0.327 AC: 477340 AN: 1459200 Hom.: 82566 Cov.: 35 AF XY: 0.331 AC XY: 240563 AN XY: 726030

Gnomad4 AFR exome AF: 0.564

Gnomad4 AMR exome AF: 0.381

Gnomad4 ASJ exome AF: 0.387

Gnomad4 EAS exome AF: 0.503

Gnomad4 SAS exome AF: 0.506

Gnomad4 FIN exome AF: 0.312

Gnomad4 NFE exome AF: 0.295

Gnomad4 OTH exome AF: 0.354

GnomAD4 genome AF: 0.392 AC: 59574 AN: 152018 Hom.: 12838 Cov.: 33 AF XY: 0.394 AC XY: 29291 AN XY: 74324

Gnomad4 AFR AF: 0.556

Gnomad4 AMR AF: 0.340

Gnomad4 ASJ AF: 0.365

Gnomad4 EAS AF: 0.556

Gnomad4 SAS AF: 0.508

Gnomad4 FIN AF: 0.322

Gnomad4 NFE AF: 0.298

Gnomad4 OTH AF: 0.373

Alfa AF: 0.323 Hom.: 18641

Bravo AF: 0.402

Asia WGS AF: 0.528 AC: 1837 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 25 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	14
Dann	Benign	0.37

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000016
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.19		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: rs6663840; hg19: chr1-3743319; COSMIC: COSV65517511; COSMIC: COSV65517511;