1-3815608-C-T

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.2663-91G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 869,724 control chromosomes in the GnomAD database, including 152,647 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (33236 hom., cov: 32)
  • Exomes 𝑓: 0.57 (119411 hom.)
• Consequence: CEP104 NM_014704.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.04

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=-0.93).
• BP6: Variant 1-3815608-C-T is Benign according to our data. Variant chr1-3815608-C-T is described in ClinVar as [Benign]. Clinvar id is 1183590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.855 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP104	NM_014704.4	c.2663-91G>A		intron_variant		ENST00000378230.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP104	ENST00000378230.8	c.2663-91G>A		intron_variant		5	NM_014704.4	P4

Frequencies

GnomAD3 genomes AF: 0.646 AC: 98149 AN: 151876 Hom.: 33180 Cov.: 32

Gnomad AFR AF: 0.862

Gnomad AMI AF: 0.559

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.660

Gnomad EAS AF: 0.557

Gnomad SAS AF: 0.679

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.553

Gnomad OTH AF: 0.606

GnomAD4 exome AF: 0.573 AC: 411582 AN: 717730 Hom.: 119411 AF XY: 0.577 AC XY: 210617 AN XY: 364882

Gnomad4 AFR exome AF: 0.867

Gnomad4 AMR exome AF: 0.506

Gnomad4 ASJ exome AF: 0.663

Gnomad4 EAS exome AF: 0.494

Gnomad4 SAS exome AF: 0.680

Gnomad4 FIN exome AF: 0.612

Gnomad4 NFE exome AF: 0.553

Gnomad4 OTH exome AF: 0.599

GnomAD4 genome AF: 0.646 AC: 98263 AN: 151994 Hom.: 33236 Cov.: 32 AF XY: 0.647 AC XY: 48043 AN XY: 74256

Gnomad4 AFR AF: 0.863

Gnomad4 AMR AF: 0.510

Gnomad4 ASJ AF: 0.660

Gnomad4 EAS AF: 0.557

Gnomad4 SAS AF: 0.679

Gnomad4 FIN AF: 0.637

Gnomad4 NFE AF: 0.553

Gnomad4 OTH AF: 0.607

Alfa AF: 0.612 Hom.: 3636

Bravo AF: 0.648

Asia WGS AF: 0.628 AC: 2184 AN: 3478

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

Genome-Nilou Lab

Jul 22, 2021

- -

not provided Benign:1

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	-0.93
Cadd	Benign	0.48
Dann	Benign	0.19

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: rs4233019; hg19: chr1-3732172; COSMIC: COSV65517132; COSMIC: COSV65517132;