rs113941736

chr7-130400746-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_018718.3(CEP41):c.718T>G(p.Cys240Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00132 in 1,613,780 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. C240C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0069 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00074 (16 hom.)
• Consequence: CEP41 NM_018718.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 7.36

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010561943).
• BP6: Variant 7-130400746-A-C is Benign according to our data. Variant chr7-130400746-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 128705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-130400746-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00693 (1056/152324) while in subpopulation AFR AF= 0.0243 (1009/41582). AF 95% confidence interval is 0.023. There are 10 homozygotes in gnomad4. There are 458 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP41	NM_018718.3	c.718T>G	p.Cys240Gly	missense_variant	9/11	ENST00000223208.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP41	ENST00000223208.10	c.718T>G	p.Cys240Gly	missense_variant	9/11	1	NM_018718.3	P3

Frequencies

GnomAD3 genomes AF: 0.00693 AC: 1055 AN: 152206 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00621

GnomAD3 exomes AF: 0.00166 AC: 417 AN: 250872 Hom.: 5 AF XY: 0.00111 AC XY: 150 AN XY: 135558

Gnomad AFR exome AF: 0.0233

Gnomad AMR exome AF: 0.000753

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000738 AC: 1079 AN: 1461456 Hom.: 16 Cov.: 30 AF XY: 0.000659 AC XY: 479 AN XY: 726994

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.000805

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.00693 AC: 1056 AN: 152324 Hom.: 10 Cov.: 32 AF XY: 0.00615 AC XY: 458 AN XY: 74490

Gnomad4 AFR AF: 0.0243

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00614

Alfa AF: 0.00119 Hom.: 1

Bravo AF: 0.00797

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00203 AC: 247

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 10, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	CEP41: BS1, BS2 -

Joubert syndrome 15 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jan 08, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	28
Dann	Uncertain	0.98
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-5.1	D;D;D
REVEL	Benign	0.28
Sift	Uncertain	0.023	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.95, 0.94	.;P;P
Vest4		0.84
MVP		0.79
MPC		0.23
ClinPred		0.020	T
GERP RS		6.0
Varity_R		0.57
gMVP		0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs113941736; hg19: chr7-130040587;