rs4648344

Variant names:

• chr1-3826568-T-C
• rs4648344
• NM_014704.4:c.2189-132A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 15 publications found

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]

CEP104 Gene-Disease associations (from GenCC):

• Joubert syndrome 25

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
CEP104	NM_014704.4	c.2189-132A>G		intron_variant	Intron 16 of 21	ENST00000378230.8	NP_055519.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP104	ENST00000378230.8	c.2189-132A>G		intron_variant	Intron 16 of 21	5	NM_014704.4	ENSP00000367476.3

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

African (AFR) AF: 0.729 AC: 19439 AN: 26666

American (AMR) AF: 0.277 AC: 11360 AN: 41036

Ashkenazi Jewish (ASJ) AF: 0.613 AC: 13890 AN: 22656

East Asian (EAS) AF: 0.0506 AC: 1907 AN: 37684

South Asian (SAS) AF: 0.406 AC: 30717 AN: 75708

European-Finnish (FIN) AF: 0.526 AC: 27306 AN: 51908

Middle Eastern (MID) AF: 0.553 AC: 2797 AN: 5056

European-Non Finnish (NFE) AF: 0.498 AC: 410452 AN: 824616

Other (OTH) AF: 0.491 AC: 24094 AN: 49116

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

African (AFR) AF: 0.715 AC: 29643 AN: 41438

American (AMR) AF: 0.375 AC: 5728 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.612 AC: 2121 AN: 3464

East Asian (EAS) AF: 0.0527 AC: 273 AN: 5180

South Asian (SAS) AF: 0.388 AC: 1873 AN: 4824

European-Finnish (FIN) AF: 0.539 AC: 5654 AN: 10492

Middle Eastern (MID) AF: 0.510 AC: 148 AN: 290

European-Non Finnish (NFE) AF: 0.495 AC: 33636 AN: 67906

Other (OTH) AF: 0.507 AC: 1070 AN: 2112

Alfa AF: 0.504 Hom.: 10238

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

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0020
DANN	Benign	0.39
PhyloP100		-0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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