5-37239730-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_001384732.1(CPLANE1):ā€‹c.817A>Cā€‹(p.Asn273His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000111 in 1,530,122 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.000012 ( 0 hom. )

Consequence

CPLANE1
NM_001384732.1 missense

Scores

7
5
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 7.39
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.777
PP5
Variant 5-37239730-T-G is Pathogenic according to our data. Variant chr5-37239730-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217593.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Pathogenic=2}. Variant chr5-37239730-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CPLANE1NM_001384732.1 linkc.817A>C p.Asn273His missense_variant Exon 7 of 53 ENST00000651892.2 NP_001371661.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CPLANE1ENST00000651892.2 linkc.817A>C p.Asn273His missense_variant Exon 7 of 53 NM_001384732.1 ENSP00000498265.2 A0A494BZW6

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152164
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.0000116
AC:
16
AN:
1377958
Hom.:
0
Cov.:
30
AF XY:
0.00000885
AC XY:
6
AN XY:
677860
show subpopulations
Gnomad4 AFR exome
AF:
0.0000321
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000140
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152164
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000301
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Joubert syndrome 17 Pathogenic:2
Feb 23, 2015
UW Hindbrain Malformation Research Program, University of Washington
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Jul 17, 2023
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) or orofaciodigital syndrome VI (MIM#277170). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to histidine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (1 heterozygote, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative 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) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least two unrelated individuals with Joubert syndrome, in whom a second hit was identified with phasing unclear (PMID: 26092869, PMID: 25407461, PMID: 29605658). It has also been classified as a VUS and as pathogenic (ClinVar). (SP) 0906 - Segregation evidence for this variant is inconclusive. This variant was identified in two affected siblings (PMID: 25407461, PMID: 29605658). (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (p.(Gln1345*)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Uncertain:1
Aug 13, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces asparagine with histidine at codon 273 of the CPLANE1 protein (p.Asn273His). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Joubert syndrome (PMID: 26092869). ClinVar contains an entry for this variant (Variation ID: 217593). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

CPLANE1-related disorder Uncertain:1
Oct 06, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The CPLANE1 c.817A>C variant is predicted to result in the amino acid substitution p.Asn273His. This variant has been reported along with a frameshift variant in an individual with Joubert syndrome (Table S5 in Bachmann-Gagescu et al. 2015. PubMed ID: 26092869). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Uncertain
0.044
T
BayesDel_noAF
Benign
-0.17
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.26
T;T
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.74
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.81
.;T
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Benign
-0.40
T
PROVEAN
Uncertain
-3.7
D;D
REVEL
Pathogenic
0.76
Sift
Pathogenic
0.0
D;D
Sift4G
Uncertain
0.0080
D;D
Vest4
0.94
MutPred
0.28
Gain of sheet (P = 0.0344);Gain of sheet (P = 0.0344);
MVP
0.77
MPC
0.58
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.71
gMVP
0.66

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.

Other links and lift over

dbSNP: rs863225167; hg19: chr5-37239832; COSMIC: COSV57063772; API