5-37244521-C-T

Variant names:

• chr5-37244521-C-T
• rs756856188
• NM_001384732.1:c.424G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PP5_Very_Strong

The NM_001384732.1(CPLANE1):​c.424G>A​(p.Glu142Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,551,530 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 U:2
• Conservation: PhyloP100: 6.93
• Publications: 2 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PP5: Variant 5-37244521-C-T is Pathogenic according to our data. Variant chr5-37244521-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 217592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384732.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	NM_001384732.1	MANE Select	c.424G>A	p.Glu142Lys	missense	Exon 5 of 53	NP_001371661.1
	CPLANE1	NM_023073.4		c.424G>A	p.Glu142Lys	missense	Exon 5 of 52	NP_075561.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CPLANE1	ENST00000651892.2	MANE Select	c.424G>A	p.Glu142Lys	missense	Exon 5 of 53	ENSP00000498265.2
	CPLANE1	ENST00000508244.5	TSL:5	c.424G>A	p.Glu142Lys	missense	Exon 4 of 51	ENSP00000421690.1
	CPLANE1	ENST00000425232.7	TSL:5	n.205G>A		non_coding_transcript_exon	Exon 2 of 30	ENSP00000389014.3

Frequencies

GnomAD3 genomes AF: 0.000132 AC: 20 AN: 151956 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000725

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: 0.000250

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000121 AC: 19 AN: 157586 AF XY: 0.0000960

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000294

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.000272 AC: 380 AN: 1399574 Hom.: 1 Cov.: 31 AF XY: 0.000252 AC XY: 174 AN XY: 690282

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35720

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.000333 AC: 359 AN: 1078978

Other (OTH) AF: 0.000362 AC: 21 AN: 58076

GnomAD4 genome AF: 0.000132 AC: 20 AN: 151956 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 74192

African (AFR) AF: 0.0000725 AC: 3 AN: 41364

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000345 Hom.: 0

Bravo AF: 0.000159

ExAC AF: 0.0000805 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Joubert syndrome 17 Pathogenic:3

Oct 27, 2020

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This CPLANE1 variant (rs756856188) is rare (<0.1%) in a large population dataset (26/188926 total alleles; 0.014%; no homozygotes) and has an entry in ClinVar. This variant has been reported previously in a compound heterozygous state in multiple unrelated individuals affected with JS. Three bioinformatics tools predict this variant would be damaging, and the glutamate residue at this position is strongly conserved across all species assessed. This variant is not predicted to affect normal exon 5 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.424G>A to be likely pathogenic.

Oct 09, 2024

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_v1.3.4, 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 VI (MIM#277170) (OMIM). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to lysine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (26 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic and pathogenic by multiple clinical laboratories in ClinVar, as well as older VUS entries. This variant has also been observed in two unrelated individuals with a second CPLANE1 variant with Joubert syndrome (PMID: 26092869). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (NM_023073.3:c.493del; p.(Ile165Tyrfs*17)) in a recessive disease. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I)

Feb 23, 2015

UW Hindbrain Malformation Research Program, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

not provided Pathogenic:3

Apr 13, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26092869)

Jul 24, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM3_strong, PS4_moderate

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 142 of the CPLANE1 protein (p.Glu142Lys). This variant is present in population databases (rs756856188, gnomAD 0.03%). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869). This variant is also known as C5ORF42 p.Glu142Lys. ClinVar contains an entry for this variant (Variation ID: 217592). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CPLANE1 protein function. For these reasons, this variant has been classified as Pathogenic.

Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17 Pathogenic:1

Jun 25, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joubert syndrome and related disorders Pathogenic:1

Aug 09, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CPLANE1 c.424G>A (p.Glu142Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 188926 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CPLANE1 causing Joubert Syndrome And Related Disorders (0.00014 vs 0.0015), allowing no conclusion about variant significance. c.424G>A has been reported in the literature in individuals affected with Joubert Syndrome who were compound heterozygous with pathogenic variants (Bachmann-Gagescu_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 26092869). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic (n=1), likely pathogenic (n=2), or uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.

CPLANE1-related disorder Pathogenic:1

Feb 21, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CPLANE1 c.424G>A variant is predicted to result in the amino acid substitution p.Glu142Lys. This variant was reported, along with a protein-truncating variant in the same gene, in two individuals with Joubert syndrome (Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). Internally, this variant was seen, in addition to a heterozygous protein-truncating variant, in two individuals who came in for testing for suspected Joubert syndrome (PreventionGenetics, internal data). This variant is reported in 0.031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/). This variant is interpreted as pathogenic.

not specified Uncertain:1

Sep 23, 2016

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

Nephronophthisis Uncertain:1

May 31, 2018

Sydney Genome Diagnostics, Children's Hospital Westmead

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This patient is also heterozygous for a variant of unknown clinical significance (VOUS), c.424G>A (p.Glu142Lys), in the C5orf42 gene. This variant (dbSNP: rs756856188) has been previously reported in the ExAC database (http://exac.broadinstitute.org/) with a very low allele frequency of 0.009% (2/22076 alleles). c.424G>A (p.Glu142Lys) 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). In silico analysis (Alamut Visual v2.8) using PolyPhen2, SIFT and Mutation Taster all predict that this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.085	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-0.41	T
PhyloP100		6.9
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D
Sift4G	Pathogenic	0.0	D
Vest4		0.92
MVP		0.67
MPC		0.61
ClinPred		0.34	T
GERP RS		5.7
Varity_R		0.53
gMVP		0.55
Mutation Taster		=180/120	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs756856188; hg19: chr5-37244623; COSMIC: COSV57059238; COSMIC: COSV57059238;