rs75589774

chr5-37182800-G-Achr5-37182800-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001384732.1(CPLANE1):c.5381C>T(p.Pro1794Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,612,254 control chromosomes in the GnomAD database, including 8,822 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (895 hom., cov: 32)
  • Exomes 𝑓: 0.10 (7927 hom.)
• Consequence: CPLANE1 NM_001384732.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.98

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013924539).
• BP6: Variant 5-37182800-G-A is Benign according to our data. Variant chr5-37182800-G-A is described in ClinVar as [Benign]. Clinvar id is 158040.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-37182800-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CPLANE1	NM_001384732.1	c.5381C>T	p.Pro1794Leu	missense_variant	26/53	ENST00000651892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CPLANE1	ENST00000651892.2	c.5381C>T	p.Pro1794Leu	missense_variant	26/53		NM_001384732.1	A2

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15839 AN: 151986 Hom.: 895 Cov.: 32

Gnomad AFR AF: 0.0875

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.140

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.0543

Gnomad SAS AF: 0.105

Gnomad FIN AF: 0.136

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.121

GnomAD3 exomes AF: 0.111 AC: 27809 AN: 250072 Hom.: 1620 AF XY: 0.110 AC XY: 14828 AN XY: 135184

Gnomad AFR exome AF: 0.0829

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.0513

Gnomad SAS exome AF: 0.101

Gnomad FIN exome AF: 0.131

Gnomad NFE exome AF: 0.106

Gnomad OTH exome AF: 0.119

GnomAD4 exome AF: 0.102 AC: 149101 AN: 1460152 Hom.: 7927 Cov.: 33 AF XY: 0.102 AC XY: 74304 AN XY: 726400

Gnomad4 AFR exome AF: 0.0849

Gnomad4 AMR exome AF: 0.152

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.0361

Gnomad4 SAS exome AF: 0.0994

Gnomad4 FIN exome AF: 0.130

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.106

GnomAD4 genome AF: 0.104 AC: 15858 AN: 152102 Hom.: 895 Cov.: 32 AF XY: 0.108 AC XY: 8005 AN XY: 74348

Gnomad4 AFR AF: 0.0876

Gnomad4 AMR AF: 0.140

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.0537

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.136

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.124

Alfa AF: 0.102 Hom.: 1404

Bravo AF: 0.103

TwinsUK AF: 0.0987 AC: 366

ALSPAC AF: 0.0872 AC: 336

ESP6500AA AF: 0.0828 AC: 365

ESP6500EA AF: 0.109 AC: 941

ExAC AF: 0.110 AC: 13324

Asia WGS AF: 0.129 AC: 446 AN: 3478

EpiCase AF: 0.116

EpiControl AF: 0.113

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 14, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -

Joubert syndrome 17 Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.029	T;T;T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.040
FATHMM_MKL	Benign	0.74	D
MetaRNN	Benign	0.0014	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.095
Sift	Benign	0.86	T;T;T
Sift4G	Benign	0.86	T;T;T
Vest4		0.11
MPC		0.14
ClinPred		0.012	T
GERP RS		4.8
Varity_R		0.076
gMVP		0.22

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

Other links and lift over

dbSNP: rs75589774; hg19: chr5-37182902; COSMIC: COSV57060255;