rs139675596

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001384732.1(CPLANE1):c.7477C>T(p.Arg2493*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,610,252 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

CPLANE1
NM_001384732.1 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8O:1

Conservation

PhyloP100: 1.26

Publications

5 publications found

Variant links:

Genes affected

CPLANE1 (HGNC:25801): (ciliogenesis and planar polarity effector complex subunit 1) The protein encoded by this gene has putative coiled-coil domains and may be a transmembrane protein. Defects in this gene are a cause of Joubert syndrome (JBTS). [provided by RefSeq, May 2012]

CPLANE1 Gene-Disease associations (from GenCC):

Joubert syndrome 17
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, G2P, Illumina, Labcorp Genetics (formerly Invitae)
orofaciodigital syndrome type 6
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CPLANE1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 5-37165595-G-A is Pathogenic according to our data. Variant chr5-37165595-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 31223.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLANE1	NM_001384732.1 link	c.7477C>T	p.Arg2493*	stop_gained	Exon 36 of 53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2 link	c.7477C>T	p.Arg2493*	stop_gained	Exon 36 of 53		NM_001384732.1	ENSP00000498265.2		A0A494BZW6

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000565

AC:

AN:

247746

AF XY:

0.0000822

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000595

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000621

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000357

AC:

AN:

1458174

Hom.:

Cov.:

AF XY:

0.0000469

AC XY:

AN XY:

725240

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33262

American (AMR)

AF:

0.0000682

AC:

AN:

43978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.000118

AC:

AN:

85098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1110830

Other (OTH)

AF:

0.0000332

AC:

AN:

60272

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41412

American (AMR)

AF:

0.00

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10574

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000547

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 17

Pathogenic:5Other:1

Apr 06, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Oct 15, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Joubert syndrome 17 (MIM#614615) and Orofaciodigital syndrome 6 (MIM#277170). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (14 heterozygotes, 0 homozygotes). (SP) 0402 - Variant is located in a gene associated with a severe early-onset recessive condition that is intolerant to bi-allelic loss of function variants (gnomAD, OMIM). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Multiple NMD-predicted variants have been reported as pathogenic or likely pathogenic in the ClinVar database. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in the compound heterozygous or homozygous state in multiple individuals with Joubert syndrome (ClinVar, PMID:22425360, 26092869, 25407461). (SP) 1206 - This variant has been shown to be paternally inherited (VCGS #20W001158, by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Dec 03, 2018

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The homozygous p.Arg2493Ter variant in C5orf42 was identified by our study in one individual with Joubert syndrome. This variant has been identified in 0.005767% (14/242764) of chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139675596). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. The p.Arg2493Ter variant in C5orf42 has been reported as a causative variant in 3 mixed European and Native American families with Joubert syndrome and in the compound heterozygous state in one individual with a missense variant, which has been reported in trans with 3 other loss of function variants (PMID: 26092869, 22425360). Loss of function of the C5orf42 gene is an established disease mechanism for autosomal recessive Joubert syndrome, and this is a loss of function variant. In summary, the p.Arg2493Ter variant is pathogenic. ACMG/AMP Criteria applied: PM2, PP3, PM3_Supporting (Richards 2015). -

Apr 11, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

not provided

Pathogenic:2

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg2493*) in the CPLANE1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CPLANE1 are known to be pathogenic (PMID: 24178751, 26092869). This variant is present in population databases (rs139675596, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with Joubert syndrome (PMID: 22425360, 26092869). ClinVar contains an entry for this variant (Variation ID: 31223). For these reasons, this variant has been classified as Pathogenic. -

Jul 19, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed with a second CPLANE1 variant on the opposite allele (in trans) in an individual with Joubert syndrome in published literature (Srour et al., 2012); Observed with a second CPLANE1 variant or in the homozygous state in four individuals with Joubert syndrome from three unrelated families (Bachmann-Gagescu et al., 2015); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22425360, 26092869, 30712878) -

Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17

Pathogenic:1

Oct 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.29

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Uncertain

0.35

Eigen_PC

Benign

0.11

FATHMM_MKL

Benign

0.40

PhyloP100

1.3

Vest4

0.24

GERP RS

4.4

Mutation Taster

=1/199

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over