dbSNP rs372708011: CEP104:p.Ala895Ser (chr1-3815497-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_014704.4(CEP104):c.2683G>T(p.Ala895Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,578 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A895V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

CEP104
NM_014704.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.88

Publications

3 publications found

Variant links:

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

CEP104 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04800588).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP104	NM_014704.4 link	c.2683G>T	p.Ala895Ser	missense_variant	Exon 22 of 22	ENST00000378230.8	NP_055519.1	O60308-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP104	ENST00000378230.8 link	c.2683G>T	p.Ala895Ser	missense_variant	Exon 22 of 22	5	NM_014704.4	ENSP00000367476.3		O60308-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000415

AC:

AN:

240938

AF XY:

0.00000767

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000915

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000206

AC:

AN:

1453578

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

722616

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33240

American (AMR)

AF:

0.00

AC:

AN:

43522

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25616

East Asian (EAS)

AF:

0.00

AC:

AN:

39552

South Asian (SAS)

AF:

0.0000118

AC:

AN:

85096

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1108414

Other (OTH)

AF:

0.00

AC:

AN:

59980

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.65

CADD

Benign

4.3

(source)

DANN

Benign

0.48

DEOGEN2

Benign

0.0033

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.96

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.44

M_CAP

Benign

0.0099

MetaRNN

Benign

0.048

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.9

PrimateAI

Benign

0.27

PROVEAN

Benign

0.31

REVEL

Benign

0.046

Sift

Benign

0.42

Sift4G

Benign

0.56

Polyphen

0.081

Vest4

0.063

MVP

0.20

MPC

0.15

ClinPred

0.057

GERP RS

4.1

Varity_R

0.027

gMVP

0.16

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over