Genetic Variant CEP41:p.Met36Lys (chr7-130416957-A-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_018718.3(CEP41):c.107T>A(p.Met36Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000007 in 1,429,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. M36T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

CEP41
NM_018718.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.32

Publications

5 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CEP41	NM_018718.3 link	c.107T>A	p.Met36Lys	missense_variant	Exon 3 of 11	ENST00000223208.10	NP_061188.1	Q9BYV8-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CEP41	ENST00000223208.10 link	c.107T>A	p.Met36Lys	missense_variant	Exon 3 of 11	1	NM_018718.3	ENSP00000223208.4		Q9BYV8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.00e-7

AC:

AN:

1429094

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713210

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32800

American (AMR)

AF:

0.00

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25914

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39552

South Asian (SAS)

AF:

0.00

AC:

AN:

85582

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53242

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1082270

Other (OTH)

AF:

0.00

AC:

AN:

59346

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.15

T;.;.;T;T;.;T

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

T;T;D;D;T;D;D

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.72

D;D;D;D;D;D;D

MetaSVM

Uncertain

0.43

MutationAssessor

Uncertain

2.4

M;M;.;.;.;.;.

PhyloP100

5.3

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.2

D;D;D;D;D;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.0020

D;D;D;D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;.;.;.;D

Polyphen

0.66

P;P;.;.;.;.;.

Vest4

0.86

MutPred

0.39

Gain of ubiquitination at M36 (P = 0.0077);Gain of ubiquitination at M36 (P = 0.0077);.;.;.;.;.;

MVP

0.92

MPC

0.11

ClinPred

0.96

GERP RS

5.7

PromoterAI

-0.011

Neutral

(source)

Varity_R

0.77

gMVP

0.62

Mutation Taster

=49/51

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over