7-130416957-A-G

Position:

chr7-130416957-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_018718.3(CEP41):c.107T>C(p.Met36Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000157 in 1,581,440 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CEP41
NM_018718.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:2U:6

Conservation

PhyloP100: 5.32

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CEP41	NM_018718.3 linkuse as main transcript	c.107T>C	p.Met36Thr	missense_variant	3/11	ENST00000223208.10	NP_061188.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CEP41	ENST00000223208.10 linkuse as main transcript	c.107T>C	p.Met36Thr	missense_variant	3/11	1	NM_018718.3	ENSP00000223208	P3	Q9BYV8-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000996

AC:

AN:

250950

Hom.:

AF XY:

0.000111

AC XY:

AN XY:

135652

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000141

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000162

AC:

231

AN:

1429090

Hom.:

Cov.:

AF XY:

0.000160

AC XY:

114

AN XY:

713208

show subpopulations

Gnomad4 AFR exome

AF:

0.000122

Gnomad4 AMR exome

AF:

0.000179

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000198

Gnomad4 OTH exome

AF:

0.0000843

GnomAD4 genome

AF:

0.000112

AC:

AN:

152350

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000177

Hom.:

Bravo

AF:

0.000121

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:2Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 15

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 03, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 28, 2016	The CEP41 c.107T>C (p.Met36Thr) variant is a missense variant that has been reported in a heterozygous state in one individual with Joubert syndrome (JS) who also carried a second heterozygous variant in another JS-associated gene (Lee et al. 2012). Digenic inheritance of JS has been previously reported (Parisi et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00014 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Met36Thr variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Joubert syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 36 of the CEP41 protein (p.Met36Thr). This variant is present in population databases (rs368178632, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of a ciliopathy spectrum disorder (PMID: 22246503). This variant is also known as p.36M>T. ClinVar contains an entry for this variant (Variation ID: 30842). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CEP41 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30664616, 22246503) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Joubert syndrome 9/15, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 15, 2012

- -

Familial Autism Spectrum Disorder

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.34

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.12

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

Eigen

Uncertain

0.31

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

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

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.32

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

MetaSVM

Uncertain

0.43

MutationAssessor

Uncertain

2.4

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

MutationTaster

Benign

0.93

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.7

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

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.012

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

Polyphen

0.21

B;P;.;.;.;.;.

Vest4

0.89

MVP

0.92

MPC

0.10

ClinPred

0.11

GERP RS

5.7

Varity_R

0.34

gMVP

0.46

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over