7-130411196-T-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.208-5A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00597 in 1,611,796 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (47 hom.)
• Consequence: CEP41 NM_018718.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001300
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.23

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 (BayesDel_noAF=-0.8).
• BP6: Variant 7-130411196-T-C is Benign according to our data. Variant chr7-130411196-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 285274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-130411196-T-C is described in Lovd as [Likely_benign]. Variant chr7-130411196-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00497 (757/152314) while in subpopulation AMR AF= 0.00693 (106/15296). AF 95% confidence interval is 0.00593. There are 6 homozygotes in gnomad4. There are 391 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR,Digenic gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CEP41	NM_018718.3	c.208-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000223208.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CEP41	ENST00000223208.10	c.208-5A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_018718.3	P3

Frequencies

GnomAD3 genomes AF: 0.00498 AC: 758 AN: 152196 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.0346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00264

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00642

Gnomad OTH AF: 0.00623

GnomAD3 exomes AF: 0.00528 AC: 1327 AN: 251206 Hom.: 13 AF XY: 0.00530 AC XY: 720 AN XY: 135772

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00338

Gnomad ASJ exome AF: 0.0328

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00300

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00603

Gnomad OTH exome AF: 0.00767

GnomAD4 exome AF: 0.00607 AC: 8859 AN: 1459482 Hom.: 47 Cov.: 29 AF XY: 0.00600 AC XY: 4354 AN XY: 726252

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00329

Gnomad4 ASJ exome AF: 0.0308

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00291

Gnomad4 FIN exome AF: 0.00266

Gnomad4 NFE exome AF: 0.00630

Gnomad4 OTH exome AF: 0.00711

GnomAD4 genome AF: 0.00497 AC: 757 AN: 152314 Hom.: 6 Cov.: 32 AF XY: 0.00525 AC XY: 391 AN XY: 74476

Gnomad4 AFR AF: 0.000890

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.0346

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00264

Gnomad4 NFE AF: 0.00642

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00626 Hom.: 3

Bravo AF: 0.00476

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00753

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	CEP41: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Joubert syndrome 15 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.31
Dann	Benign	0.63

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00013
dbscSNV1_RF	Benign	0.032
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

Other links and lift over

dbSNP: rs11765434; hg19: chr7-130051037;