rs4648344

Positions:

• chr1-3826568-T-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.2189-132A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,286,342 control chromosomes in the GnomAD database, including 159,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (23041 hom., cov: 34)
  • Exomes 𝑓: 0.48 (136367 hom.)
• Consequence: CEP104 NM_014704.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.863

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=-0.89).
• BP6: Variant 1-3826568-T-C is Benign according to our data. Variant chr1-3826568-T-C is described in ClinVar as [Benign]. Clinvar id is 1222061.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP104	NM_014704.4	c.2189-132A>G		intron_variant		ENST00000378230.8	NP_055519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP104	ENST00000378230.8	c.2189-132A>G		intron_variant		5	NM_014704.4	ENSP00000367476	P4

Frequencies

GnomAD3 genomes AF: 0.531 AC: 80553 AN: 151778 Hom.: 22999 Cov.: 34

Gnomad AFR AF: 0.715

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.376

Gnomad ASJ AF: 0.612

Gnomad EAS AF: 0.0522

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.539

Gnomad MID AF: 0.497

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.510

GnomAD4 exome AF: 0.478 AC: 541962 AN: 1134446 Hom.: 136367 Cov.: 15 AF XY: 0.477 AC XY: 274190 AN XY: 575420

Gnomad4 AFR exome AF: 0.729

Gnomad4 AMR exome AF: 0.277

Gnomad4 ASJ exome AF: 0.613

Gnomad4 EAS exome AF: 0.0506

Gnomad4 SAS exome AF: 0.406

Gnomad4 FIN exome AF: 0.526

Gnomad4 NFE exome AF: 0.498

Gnomad4 OTH exome AF: 0.491

GnomAD4 genome AF: 0.531 AC: 80648 AN: 151896 Hom.: 23041 Cov.: 34 AF XY: 0.523 AC XY: 38841 AN XY: 74228

Gnomad4 AFR AF: 0.715

Gnomad4 AMR AF: 0.375

Gnomad4 ASJ AF: 0.612

Gnomad4 EAS AF: 0.0527

Gnomad4 SAS AF: 0.388

Gnomad4 FIN AF: 0.539

Gnomad4 NFE AF: 0.495

Gnomad4 OTH AF: 0.507

Alfa AF: 0.504 Hom.: 9231

Bravo AF: 0.527

Asia WGS AF: 0.246 AC: 856 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0020
DANN	Benign	0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs4648344; hg19: chr1-3743132; COSMIC: COSV65517148; COSMIC: COSV65517148;