rs147444165

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_018718.3(CEP41):c.1009T>C(p.Ser337Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000426 in 1,614,066 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0020 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00026 ( 2 hom. )

Consequence

CEP41
NM_018718.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 0.151

Publications

6 publications found

Variant links:

Genes affected

CEP41 (HGNC:12370): (centrosomal protein 41) This gene encodes a centrosomal and microtubule-binding protein which is predicted to have two coiled-coil domains and a rhodanese domain. In human retinal pigment epithelial cells the protein localized to centrioles and cilia. Mutations in this gene have been associated with Joubert Syndrome 15; an autosomal recessive ciliopathy and neurological disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

CEP41 Gene-Disease associations (from GenCC):

Joubert syndrome 15
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Joubert syndrome with ocular defect
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CEP41 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067655146).

BP6

Variant 7-130399004-A-G is Benign according to our data. Variant chr7-130399004-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 358939.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00205 (312/152230) while in subpopulation AFR AF = 0.00703 (292/41536). AF 95% confidence interval is 0.00637. There are 1 homozygotes in GnomAd4. There are 151 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP41	NM_018718.3 link	c.1009T>C	p.Ser337Pro	missense_variant	Exon 11 of 11	ENST00000223208.10	NP_061188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP41	ENST00000223208.10 link	c.1009T>C	p.Ser337Pro	missense_variant	Exon 11 of 11	1	NM_018718.3	ENSP00000223208.4

Frequencies

GnomAD3 genomes

AF:

0.00202

AC:

307

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00693

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.000593

AC:

149

AN:

251110

AF XY:

0.000442

show subpopulations

Gnomad AFR exome

AF:

0.00634

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000969

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000257

AC:

375

AN:

1461836

Hom.:

Cov.:

AF XY:

0.000226

AC XY:

164

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.00759

AC:

254

AN:

33480

American (AMR)

AF:

0.000783

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1112002

Other (OTH)

AF:

0.000844

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00205

AC:

312

AN:

152230

Hom.:

Cov.:

AF XY:

0.00203

AC XY:

151

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00703

AC:

292

AN:

41536

American (AMR)

AF:

0.000850

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68006

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000714

Hom.:

Bravo

AF:

0.00244

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000717

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Oct 10, 2019

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CEP41: BP4, BS2 -

Joubert syndrome 15

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Jan 09, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CEP41-related disorder

Benign:1

Nov 05, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.043

.;T;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.80

T;T;T

M_CAP

Benign

0.077

MetaRNN

Benign

0.0068

T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Uncertain

2.0

.;M;.

PhyloP100

0.15

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.25

N;N;N

REVEL

Benign

0.26

Sift

Benign

0.22

T;D;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.68, 0.53

.;P;P

Vest4

0.11

MVP

0.83

MPC

0.23

ClinPred

0.040

GERP RS

-1.6

Varity_R

0.13

gMVP

0.45

Mutation Taster

=81/19

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over