Variant rs777686211 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001384732.1(CPLANE1):c.1819delT(p.Tyr607fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.000178 in 1,539,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CPLANE1
NM_001384732.1 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:18

Conservation

PhyloP100: 4.24

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 links:

CPLANE1 (HGNC:):

CPLANE1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 5-37226775-TA-T is Pathogenic according to our data. Variant chr5-37226775-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37226775-TA-T is described in Lovd as [Pathogenic]. Variant chr5-37226775-TA-T is described in Lovd as [Likely_pathogenic]. Variant chr5-37226775-TA-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPLANE1	NM_001384732.1 linkuse as main transcript	c.1819delT	p.Tyr607fs	frameshift_variant	12/53	ENST00000651892.2	NP_001371661.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CPLANE1	ENST00000651892.2 linkuse as main transcript	c.1819delT	p.Tyr607fs	frameshift_variant	12/53		NM_001384732.1	ENSP00000498265.2		A0A494BZW6

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000324

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000161

AC:

AN:

142536

Hom.:

AF XY:

0.000226

AC XY:

AN XY:

75282

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000236

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000975

Gnomad SAS exome

AF:

0.0000518

Gnomad FIN exome

AF:

0.000123

Gnomad NFE exome

AF:

0.000231

Gnomad OTH exome

AF:

0.000253

GnomAD4 exome

AF:

0.000179

AC:

248

AN:

1387796

Hom.:

Cov.:

AF XY:

0.000196

AC XY:

134

AN XY:

683914

show subpopulations

Gnomad4 AFR exome

AF:

0.0000974

Gnomad4 AMR exome

AF:

0.000211

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000130

Gnomad4 FIN exome

AF:

0.000285

Gnomad4 NFE exome

AF:

0.000198

Gnomad4 OTH exome

AF:

0.000174

GnomAD4 genome

AF:

0.000171

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.000135

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.000324

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000145

Hom.:

Bravo

AF:

0.000193

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2024	Frameshift 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; This variant is associated with the following publications: (PMID: 28125082, 34008892, 26092869, 34313030, Shelby[2022]casereport) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	CPLANE1: PVS1, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2021	This sequence change creates a premature translational stop signal (p.Tyr607Thrfs*6) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individuals with Joubert syndrome (PMID: 26092869, 28125082). ClinVar contains an entry for this variant (Variation ID: 217590). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Sep 23, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Joubert syndrome 17

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	This variant was identified as compound heterozygous. -
Pathogenic, criteria provided, single submitter	research	UW Hindbrain Malformation Research Program, University of Washington	Feb 23, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Sep 15, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 26, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 10, 2021	PVS1, PM2, PP3, PP5 -

Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Feb 05, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jun 30, 2021	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 02, 2021

The c.1819delT (p.Y607Tfs*6) alteration, located in exon 12 (coding exon 11) of the C5orf42 gene, consists of a deletion of one nucleotide at position 1819, causing a translational frameshift with a predicted alternate stop codon after 6 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in the compound heterozygous state with a second C5orf42 alteration in a patient with Joubert syndrome (Bachmann-Gagescu, 2015). Based on the available evidence, this alteration is classified as pathogenic. -

Nephronophthisis

Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Sydney Genome Diagnostics, Children's Hospital Westmead

May 31, 2018

This patient is heterozygous for a likely pathogenic variant, c.1819del, in the C5orf42 gene. c.1819del (dbSNP: rs777686211) has been reported in the ExAC database (http://exac.broadinstitute.org/) with a low allele frequency of 0.024% (5/20526 alleles) and has also been reported as a compound heterozygous variant in a patient with Joubert syndrome (Bachmann-Gagescu et al. J.Med.Genet 2015; 52:514-522). This frameshifting variant is predicted to create a premature stop codon (p.Tyr607Thrfs*6) and may result in a null allele due to nonsense-mediated mRNA decay. This variant is considered to be a likely pathogenic according to the ACMG guidelines. -

Jaundice;C0557874:Global developmental delay

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Nov 28, 2013

- -

Orofaciodigital syndrome type 6

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 18, 2019

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -

CPLANE1-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 08, 2024

The CPLANE1 c.1819delT variant is predicted to result in a frameshift and premature protein termination (p.Tyr607Thrfs*6). This variant has previously been reported in the compound heterozygous state in individuals with Joubert syndrome (Bachmann-Gagescu et al. 2015. PubMed ID: 26092869; Table 1, Vilboux T et al 2017. PubMed ID: 28125082). This variant is reported in 0.024% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CPLANE1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

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