rs147426388

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

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. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CPLANE1	NM_001384732.1 linkuse as main transcript	c.8678C>T	p.Pro2893Leu	missense_variant	46/53	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.8678C>T	p.Pro2893Leu	missense_variant	46/53		NM_001384732.1	ENSP00000498265	A2

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

GnomAD3 exomes

AF:

0.000446

AC:

109

AN:

244274

Hom.:

AF XY:

0.000402

AC XY:

AN XY:

131868

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 SAS exome

AF:

0.0000352

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

Gnomad4 AFR exome

AF:

0.0000602

Gnomad4 AMR exome

AF:

0.000606

Gnomad4 ASJ exome

AF:

0.000424

Gnomad4 EAS exome

AF:

0.000152

Gnomad4 SAS exome

AF:

0.0000831

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000778

Gnomad4 OTH exome

AF:

0.000432

GnomAD4 genome

AF:

0.000453

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000336

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.000577

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000567

Gnomad4 NFE

AF:

0.000676

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000450

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

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 13, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Oct 20, 2022

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Joubert syndrome 17

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2023

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

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

MutationTaster

Benign

0.85

N;N;N

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

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

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