chr7-130411196-T-C

Variant names:

• chr7-130411196-T-C
• rs11765434
• NM_018718.3:c.208-5A>G

Variant summary

Our verdict is Benign. The variant received -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, 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, intron
• Scores: Splicing: ADA: 0.0001300
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -2.23
• Publications: 2 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 285274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018718.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP41	NM_018718.3	MANE Select	c.208-5A>G		splice_region intron	N/A	NP_061188.1
	CEP41	NM_001257158.2		c.208-5A>G		splice_region intron	N/A	NP_001244087.1
	CEP41	NM_001257159.2		c.160-5A>G		splice_region intron	N/A	NP_001244088.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CEP41	ENST00000223208.10	TSL:1 MANE Select	c.208-5A>G		splice_region intron	N/A	ENSP00000223208.4
	CEP41	ENST00000343969.10	TSL:1	c.208-5A>G		splice_region intron	N/A	ENSP00000342738.6
	CEP41	ENST00000484549.6	TSL:1	n.*380-5A>G		splice_region intron	N/A	ENSP00000419078.2

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

GnomAD2 exomes AF: 0.00528 AC: 1327 AN: 251206 AF XY: 0.00530

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 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

African (AFR) AF: 0.00102 AC: 34 AN: 33438

American (AMR) AF: 0.00329 AC: 147 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0308 AC: 804 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00291 AC: 251 AN: 86206

European-Finnish (FIN) AF: 0.00266 AC: 142 AN: 53392

Middle Eastern (MID) AF: 0.0104 AC: 60 AN: 5764

European-Non Finnish (NFE) AF: 0.00630 AC: 6992 AN: 1109852

Other (OTH) AF: 0.00711 AC: 429 AN: 60314

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

African (AFR) AF: 0.000890 AC: 37 AN: 41566

American (AMR) AF: 0.00693 AC: 106 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0346 AC: 120 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4828

European-Finnish (FIN) AF: 0.00264 AC: 28 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00642 AC: 437 AN: 68042

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00584 Hom.: 4

Bravo AF: 0.00476

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00769

EpiControl AF: 0.00753

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	2	Joubert syndrome 15 (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.31
DANN	Benign	0.63
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs11765434; hg19: chr7-130051037;