rs6663840

Variant names:

• chr1-3826755-G-A
• rs6663840
• NM_014704.4:c.2152-11C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-3826755-G-A
• chr1-3826755-G-C

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.2152-11C>T variant causes a 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 intron
• Scores: Splicing: ADA: 0.00001617
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.184
• Publications: 25 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):

• ciliopathy

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Joubert syndrome 25

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• 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=-0.87).
• BP6: Variant 1-3826755-G-A is Benign according to our data. Variant chr1-3826755-G-A is described in ClinVar as Benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014704.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP104	NM_014704.4	MANE Select	c.2152-11C>T		intron	N/A	NP_055519.1	O60308-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP104	ENST00000378230.8	TSL:5 MANE Select	c.2152-11C>T		intron	N/A	ENSP00000367476.3	O60308-1
	CEP104	ENST00000675666.1		c.2152-11C>T		intron	N/A	ENSP00000502548.1	A0A6Q8PH69
	CEP104	ENST00000676052.1		c.2170-11C>T		intron	N/A	ENSP00000502793.1	A0A6Q8PHR0

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

GnomAD2 exomes AF: 0.381 AC: 95695 AN: 251236 AF XY: 0.380

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 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

African (AFR) AF: 0.564 AC: 18853 AN: 33418

American (AMR) AF: 0.381 AC: 17044 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.387 AC: 10101 AN: 26108

East Asian (EAS) AF: 0.503 AC: 19961 AN: 39692

South Asian (SAS) AF: 0.506 AC: 43615 AN: 86188

European-Finnish (FIN) AF: 0.312 AC: 16649 AN: 53406

Middle Eastern (MID) AF: 0.415 AC: 2391 AN: 5764

European-Non Finnish (NFE) AF: 0.295 AC: 327388 AN: 1109620

Other (OTH) AF: 0.354 AC: 21338 AN: 60294

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

African (AFR) AF: 0.556 AC: 23041 AN: 41428

American (AMR) AF: 0.340 AC: 5189 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.365 AC: 1267 AN: 3468

East Asian (EAS) AF: 0.556 AC: 2879 AN: 5178

South Asian (SAS) AF: 0.508 AC: 2450 AN: 4824

European-Finnish (FIN) AF: 0.322 AC: 3397 AN: 10566

Middle Eastern (MID) AF: 0.310 AC: 91 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20243 AN: 67960

Other (OTH) AF: 0.373 AC: 788 AN: 2112

Alfa AF: 0.336 Hom.: 31151

Bravo AF: 0.402

Asia WGS AF: 0.528 AC: 1837 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Joubert syndrome 25 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	14
DANN	Benign	0.37
PhyloP100		0.18
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6663840; hg19: chr1-3743319; COSMIC: COSV65517511; COSMIC: COSV65517511;