dbSNP rs777686211: CPLANE1:p.Tyr607ThrfsTer6 (chr5-37226775-TA-T) – ACMG Classification: Pathogenic (18 pts)

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.Tyr607ThrfsTer6) 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:19

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:

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 rank	MANE	Protein	UniProt
CPLANE1	NM_001384732.1 link	c.1819delT	p.Tyr607ThrfsTer6	frameshift_variant	Exon 12 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.1819delT	p.Tyr607ThrfsTer6	frameshift_variant	Exon 12 of 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:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Joubert syndrome 17

Pathogenic:6

Sep 15, 2020

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Laboratory of Medical Genetics, National & Kapodistrian University of Athens

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2, PP3, PP5 -

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Aug 26, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 20, 2024

Cytogenetics and Genomics Lab, Cyprus Institute Of Neurology and Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

This is a null variant in a gene where loss-of-function is a known mechnism of disease (PVS1_very strong). It is also found in extremely low frequency in gnomAD population databases (PM2_supporting). The variant was found in compound heterozygous state with NM_001384732.1:c.8633-4_8633-3del. -

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as compound heterozygous. -

not provided

Pathogenic:6

Sep 23, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

Jan 20, 2025

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.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. -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CPLANE1: PVS1, PM2, PM3 -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17

Pathogenic:2

Jun 30, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 05, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Sep 02, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 31, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Nov 28, 2013

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CPLANE1-related disorder

Pathogenic:1

Jan 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Orofaciodigital syndrome type 6

Pathogenic:1

Apr 18, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

Other links and lift over