rs147426388

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_001384732.1(CPLANE1):c.8678C>T(p.Pro2893Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000636 in 1,607,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P2893P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00045 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00066 ( 0 hom. )

Consequence

CPLANE1
NM_001384732.1 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.12

Publications

7 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: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.044307053).

BP6

Variant 5-37138834-G-A is Benign according to our data. Variant chr5-37138834-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 353421.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPLANE1	NM_001384732.1 link	c.8678C>T	p.Pro2893Leu	missense_variant	Exon 46 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.8678C>T	p.Pro2893Leu	missense_variant	Exon 46 of 53		NM_001384732.1	ENSP00000498265.2

Frequencies

GnomAD3 genomes

AF:

0.000454

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.000577

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000567

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.000446

AC:

109

AN:

244274

AF XY:

0.000402

show subpopulations

Gnomad AFR exome

AF:

0.000249

Gnomad AMR exome

AF:

0.000647

Gnomad ASJ exome

AF:

0.000815

Gnomad EAS exome

AF:

0.000276

Gnomad FIN exome

AF:

0.000232

Gnomad NFE exome

AF:

0.000563

Gnomad OTH exome

AF:

0.000335

GnomAD4 exome

AF:

0.000656

AC:

954

AN:

1455072

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

467

AN XY:

723516

show subpopulations

African (AFR)

AF:

0.0000602

AC:

AN:

33196

American (AMR)

AF:

0.000606

AC:

AN:

42874

Ashkenazi Jewish (ASJ)

AF:

0.000424

AC:

AN:

25914

East Asian (EAS)

AF:

0.000152

AC:

AN:

39482

South Asian (SAS)

AF:

0.0000831

AC:

AN:

84262

European-Finnish (FIN)

AF:

0.000150

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.000697

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.000778

AC:

864

AN:

1110060

Other (OTH)

AF:

0.000432

AC:

AN:

60180

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

136

182

227

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

102

136

170

<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:

0.000453

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41550

American (AMR)

AF:

0.000327

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000577

AC:

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.000567

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68016

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

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:

0.000479

Hom.:

Bravo

AF:

0.000344

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000420

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A variant of uncertain significance has been identified in the C5orf42 gene. The P2839L variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 8/9894 (0.08%) alleles from individuals of Ashkenazi Jewish background in large population cohorts (Lek et al., 2016). The P2839L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

not specified

Uncertain:1

Oct 20, 2022

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CPLANE1 c.8516C>T (p.Pro2839Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 275666 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CPLANE1 causing Joubert Syndrome And Related Disorders (0.00046 vs 0.0015), allowing no conclusion about variant significance. c.8516C>T has not been reported in the literature in individuals affected with Joubert Syndrome And Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Orofaciodigital syndrome type 6;C3553264:Joubert syndrome 17

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joubert syndrome 17

Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Uncertain:1

Aug 03, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.8516C>T (p.P2839L) alteration is located in exon 45 (coding exon 44) of the C5orf42 gene. This alteration results from a C to T substitution at nucleotide position 8516, causing the proline (P) at amino acid position 2839 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.18

T;T;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.82

.;T;T

M_CAP

Benign

0.039

MetaRNN

Benign

0.044

T;T;T

MetaSVM

Benign

-0.90

PhyloP100

1.1

PROVEAN

Uncertain

-2.7

D;D;D

REVEL

Benign

0.049

Sift

Uncertain

0.010

D;D;D

Sift4G

Uncertain

0.013

D;D;D

Vest4

0.27

MVP

0.44

MPC

0.46

ClinPred

0.039

GERP RS

1.9

Varity_R

0.065

gMVP

0.14

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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